Rethinking the Use of Antidepressants to Treat Alcohol Use Disorders and Depression Comorbidity: The Role of Neurogenesis

*Antonio Ballesta, Francisco Alén, Fernando Rodríguez de Fonseca, Raquel Gómez de Heras and Laura Orio*

#### **Abstract**

Patients with alcohol use disorders (AUDs) are frequently treated with antidepressant drugs (ADs), but clinical evidence of their efficacy is contradictory. Considering that ADs are thought to produce their therapeutic effects partially by increasing hippocampal plasticity and neurogenesis (HN), and that both AUDs and depression share a potential for the disruption of these neuroplastic processes, one could reasonably wonder whether the poor efficacy of AD treatment could be explained by the inability of these drugs to exert their proper action in patients suffering from AUD or depression. In order to further clarify this question, this chapter aims to examine available data regarding the effect of ADs on behavioral and HN alterations related to alcohol abstinence, as a key period in which the treatment would be implemented and in which their potential effects on alcohol-related problems remain under controversy.

**Keywords:** alcohol use disorders (AUDs), antidepressants (ADs), hippocampal neurogenesis (HN), depression, comorbidity, alcohol withdrawal

#### **1. Introduction**

AUD is a chronic relapsing brain disease characterized by the presence of various symptoms, such as physically hazardous alcohol drinking, tolerance, withdrawal, or craving related to alcohol consumption, whereas MD is a psychiatric disorder characterized by low mood, anhedonia, insomnia, low motivation, apathy, and feelings of guilt, among other symptoms [1]. Epidemiological studies have shown a strong relationship between alcohol use disorders (AUDs) and depression. Indeed, the prevalence of current or lifetime alcohol problems in depression is estimated around 16% and 30%, respectively [2].

Adult hippocampal neurogenesis (HN) is a complex multistep process by which neural progenitor cells (NPCs) divide throughout life and give rise to new functional neurons in restricted regions of the adult mammalian brain (**Figure 1**, and also described in [3]). The dentate gyrus of the hippocampus is one of the brain areas that respond to stimuli through multiple mechanisms that allow the proliferation,

#### **Figure 1.**

*Schematic representation of the stages of adult hippocampal neurogenesis in the subgranular zone of the dentate gyrus and the main immunolabeling techniques used in the cited studies.*

maturation, and integration of new generated neurons in this structure, an event that appears to regulate and improve impaired cognition and mood in various disorders [4]. Both AUDs and depression have shown to compromise HN processes [5, 6]. The HN theory of depression sustains that depression results from impaired adult HN, and, therefore, its restoration leads to recovery [7]. Direct causality of HN alterations in the pathogenesis of depression seems unlikely [8], but the clinical relevance of hippocampal newly generated neurons in depression continues to be the object of study [9]. In addition, HN and plasticity processes have been proposed as a possible common neurobiological mechanism underlying alcohol withdrawal and depression [10]. In fact, HN has been proposed to significantly contribute to alcoholic pathology, although the mechanisms of alcohol-induced alterations in HN are not completely understood [6]. In this sense, there is strong evidence in animal models that alcoholic neuropathology is at least partially due to an attenuation of adult HN induced by intoxication, a state that could be reversed by spontaneous reactive HN processes during abstinence [11]. In this regard, authors have proposed that while suppression of hippocampal neurogenic proliferation appears to be a factor of comorbid vulnerability, enhancing HN into the neural circuits affected by drug may contribute to recovery [12, 13].

Antidepressants (ADs), mainly selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs), are the primary pharmacological treatment indicated for depression-diagnosed patients [14]. Concurrently, evidence of monoamine alterations in AUDs has encouraged the investigation of drugs that act on the serotonin system to treat alcohol abuse [15]. Only a few drugs with clear evidence but modest effects are approved for treatment of AUDs, as naltrexone and acamprosate, although given certain clinical circumstances, substance use disorders may require specific treatment; thus, off-label medications like ADs are also frequently prescribed, mainly in AUD depressed patients [16]. At first, the monoamine theory of depression is based on the fact that brain monoamine systems appear to regulate mood and traditional ADs, such as SSRI, and selectively increase monoamine signaling in neural pathways related to mood regulation [17]. Later, at the beginning of the century, different results supported the hypothesis that ADs might affect mood by increasing adult HN [18]. At the same time, numerous studies have led to propose that ADs can influence HN by serotonin modulation and that HN may be related to AD effects (reviewed in [19]). In agreement, postmortem studies have reported

**19**

*Rethinking the Use of Antidepressants to Treat Alcohol Use Disorders and Depression…*

extent to which it participates in recovery in the treatment with ADs [26].

key to the etiology and maintenance of the pathophysiology of addiction [28].

**2.1 Clinical and preclinical evidence of AUD contribution to depressive** 

Authors have considered whether there may be a causal relationship between AUDs and depression and whether one of the disorders can lead to the appearance of the other. Thus, numerous studies reveal ample evidence of the risk of depression resulting from AUDs [29]. Moreover, problematic patterns of alcohol consumption are related to depressive symptomatology, both in adult and adolescent populations [30, 31]. In an attempt to simplify the complexities of the relation between AUDs and depression, a classification of depression as primary or secondary according to whether it developed before or after the onset of the AUD was proposed. The term independent (ID) was used for a depression that began before the onset of alcohol dependence or during sustained (at least 4 weeks) abstinence, while depressive syndromes occurring only during a period of active alcohol dependence were labeled as substance-induced (SID) [32]**.** However, some of the depressive symptoms classified as ID could actually be substance-induced, as SID appears not to be a stable diagnosis, with about one quarter of patients initially labeled with SID meeting criteria for ID within the next 12 months [33]. Thus, SID would be considered a self-limiting condition that would tend to remit with abstinence, while ID would require specific depression treatment [32]. After receiving treatment for alcohol consumption, those with SID would show better depression outcomes and reduce their drinking more than those with ID [32]. Also, and further supporting a causal role of alcohol consumption in depression, reducing its consumption would improve the outcomes for both types of depression [34]. In the same sense, some authors have proposed that reducing hazardous drinking can improve depressive symptoms, but continued hazardous use slows

**2.2 Preclinical evidence of the contribution of alcohol to depressive-like behavior**

Animal studies might overcome the limitations of the clinical studies, allowing to obtain not only correlative information but also contributing data that would

Data from AUD patients have led to the proposal that the effective components of withdrawal, such as dysphoria and depressed mood, create a motivational drive that leads to compulsive ethanol drinking behavior even after long periods of abstinence [27]. Subsequent findings promoted the hypothesis that drugs of abuse elicit pronounced euphoria followed by a negative emotional state that can disrupt homeostasis, considered

that ADs augment NPC numbers [20, 21] and restore mature hippocampal neural population and dentate gyrus volume of depressed patients [22, 23]. These human data reflect the neurogenic potential of ADs previously reported in animals [24]. In this respect, animal studies have led to suggest that, while not causally involved in the onset of depression, HN has been related to the ability of chronic monoaminergic ADs to achieve recovery [8]**.** Recent studies have reopened the debate about the functional implication of adult HN in humans (see [25]), highlighting the need to further study the generation of new neurons in the adult human hippocampus. This also implies to characterize the role of HN in depression and AUDs [4, 6] and the

*DOI: http://dx.doi.org/10.5772/intechopen.83743*

**2. Alcohol use disorders and depression**

**symptomatology**

recovery for psychiatric patients [35].

*Rethinking the Use of Antidepressants to Treat Alcohol Use Disorders and Depression… DOI: http://dx.doi.org/10.5772/intechopen.83743*

that ADs augment NPC numbers [20, 21] and restore mature hippocampal neural population and dentate gyrus volume of depressed patients [22, 23]. These human data reflect the neurogenic potential of ADs previously reported in animals [24]. In this respect, animal studies have led to suggest that, while not causally involved in the onset of depression, HN has been related to the ability of chronic monoaminergic ADs to achieve recovery [8]**.** Recent studies have reopened the debate about the functional implication of adult HN in humans (see [25]), highlighting the need to further study the generation of new neurons in the adult human hippocampus. This also implies to characterize the role of HN in depression and AUDs [4, 6] and the extent to which it participates in recovery in the treatment with ADs [26].

#### **2. Alcohol use disorders and depression**

*Antidepressants - Preclinical, Clinical and Translational Aspects*

maturation, and integration of new generated neurons in this structure, an event that appears to regulate and improve impaired cognition and mood in various disorders [4]. Both AUDs and depression have shown to compromise HN processes [5, 6]. The HN theory of depression sustains that depression results from impaired adult HN, and, therefore, its restoration leads to recovery [7]. Direct causality of HN alterations in the pathogenesis of depression seems unlikely [8], but the clinical relevance of hippocampal newly generated neurons in depression continues to be the object of study [9]. In addition, HN and plasticity processes have been proposed as a possible common neurobiological mechanism underlying alcohol withdrawal and depression [10]. In fact, HN has been proposed to significantly contribute to alcoholic pathology, although the mechanisms of alcohol-induced alterations in HN are not completely understood [6]. In this sense, there is strong evidence in animal models that alcoholic neuropathology is at least partially due to an attenuation of adult HN induced by intoxication, a state that could be reversed by spontaneous reactive HN processes during abstinence [11]. In this regard, authors have proposed that while suppression of hippocampal neurogenic proliferation appears to be a factor of comorbid vulnerability, enhancing HN into the neural circuits affected by drug may contribute to recovery [12, 13].

*Schematic representation of the stages of adult hippocampal neurogenesis in the subgranular zone of the* 

*dentate gyrus and the main immunolabeling techniques used in the cited studies.*

Antidepressants (ADs), mainly selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs), are the primary pharmacological treatment indicated for depression-diagnosed patients [14]. Concurrently, evidence of monoamine alterations in AUDs has encouraged the investigation of drugs that act on the serotonin system to treat alcohol abuse [15]. Only a few drugs with clear evidence but modest effects are approved for treatment of AUDs, as naltrexone and acamprosate, although given certain clinical circumstances, substance use disorders may require specific treatment; thus, off-label medications like ADs are also frequently prescribed, mainly in AUD depressed patients [16]. At first, the monoamine theory of depression is based on the fact that brain monoamine systems appear to regulate mood and traditional ADs, such as SSRI, and selectively increase monoamine signaling in neural pathways related to mood regulation [17]. Later, at the beginning of the century, different results supported the hypothesis that ADs might affect mood by increasing adult HN [18]. At the same time, numerous studies have led to propose that ADs can influence HN by serotonin modulation and that HN may be related to AD effects (reviewed in [19]). In agreement, postmortem studies have reported

**18**

**Figure 1.**

Data from AUD patients have led to the proposal that the effective components of withdrawal, such as dysphoria and depressed mood, create a motivational drive that leads to compulsive ethanol drinking behavior even after long periods of abstinence [27]. Subsequent findings promoted the hypothesis that drugs of abuse elicit pronounced euphoria followed by a negative emotional state that can disrupt homeostasis, considered key to the etiology and maintenance of the pathophysiology of addiction [28].

#### **2.1 Clinical and preclinical evidence of AUD contribution to depressive symptomatology**

Authors have considered whether there may be a causal relationship between AUDs and depression and whether one of the disorders can lead to the appearance of the other. Thus, numerous studies reveal ample evidence of the risk of depression resulting from AUDs [29]. Moreover, problematic patterns of alcohol consumption are related to depressive symptomatology, both in adult and adolescent populations [30, 31]. In an attempt to simplify the complexities of the relation between AUDs and depression, a classification of depression as primary or secondary according to whether it developed before or after the onset of the AUD was proposed. The term independent (ID) was used for a depression that began before the onset of alcohol dependence or during sustained (at least 4 weeks) abstinence, while depressive syndromes occurring only during a period of active alcohol dependence were labeled as substance-induced (SID) [32]**.** However, some of the depressive symptoms classified as ID could actually be substance-induced, as SID appears not to be a stable diagnosis, with about one quarter of patients initially labeled with SID meeting criteria for ID within the next 12 months [33]. Thus, SID would be considered a self-limiting condition that would tend to remit with abstinence, while ID would require specific depression treatment [32]. After receiving treatment for alcohol consumption, those with SID would show better depression outcomes and reduce their drinking more than those with ID [32]. Also, and further supporting a causal role of alcohol consumption in depression, reducing its consumption would improve the outcomes for both types of depression [34]. In the same sense, some authors have proposed that reducing hazardous drinking can improve depressive symptoms, but continued hazardous use slows recovery for psychiatric patients [35].

#### **2.2 Preclinical evidence of the contribution of alcohol to depressive-like behavior**

Animal studies might overcome the limitations of the clinical studies, allowing to obtain not only correlative information but also contributing data that would

allow a larger approach to the possible underlying causes in the relation of the AUD and depression. Several preclinical studies have assessed behavioral alterations during acute withdrawal and/or protracted abstinence in different animal models of alcohol abuse [36–47]. Studies used rodents as experimental animals, and the majority used the AUD model of chronic intermittent ethanol (CIE) vapor exposure. Behavioral analysis was carried out from a few hours (less than 24 hours) to several days or weeks after the last alcohol consumption, using the forced swimming test (FST) the most frequently used paradigm for this purpose. FST allows detecting responses toward an inescapable stress in animals based on the measurement of the time they remain immobile rather than displaying active strategies, akin to responses that would be impaired in depression. This response has been commonly described in the literature as depressive-like behavior. Affective alterations induced by alcohol were generally detected once alcohol exposure ceased, regardless of the animal model used, with few exceptions. It is interesting to note that studies evaluating both acute and chronic abstinence found occurrence of depressive-like behavior in both experimental periods although mostly after prolonged abstinence, which may indicate that the negative affective state as a consequence of abstinence, especially when maintained for prolonged periods, might be a risk factor for displaying depressive-like behavior, analogous to the way in which depression manifests itself in abstinent AUD patients.

#### **2.3 Depression contributes to the risk of alcohol relapse**

As previously mentioned, a negative affective state is not only a consequence of consumption but also could represent a maintenance factor for the addiction cycle [28]. In coherence, the "self-medication" theory postulates that the desire to avoid or alleviate preexisting or abstinence-related aversive states is a determining factor of excessive drug use and relapse [48]. Relapse is one of the most complicated components of drug addiction and involves a complex interaction of drug-associated cues that respond to multiple biological, psychiatric, psychological, and psychosocial factors which may precipitate the restoration of consumption [49, 50]. Therefore, one of the main goals in treating substance abuse is to preserve abstinence.

#### **2.4 Clinical evidence of depressive symptomatology contributing to the risk of alcohol relapse**

Clinical data strongly support the relevance of negative emotionality in protracted abstinence and relapse. Thus, for example, a higher prevalence of depressed mood has been observed in AUD patients who relapsed [51]. Depression-related low motivation has been shown to precipitate alcohol relapse, while improvements contributed to greater abstinence [52–55]. In fact, those studies have emphasized the need to treat depression to preserve abstinence and improve outcome of patients with AUD. We mentioned before that the AUD can contribute to an ID or a SID. Thus, some authors wonder whether transient symptomatology (SID) would affect consumption in the same way as the observed ID in prolonged abstinence. In this sense, it has been suggested that while affective dysregulation in protracted abstinence is likely to be of immediate relevance for relapse to excessive alcohol use, the link between the early withdrawal phenomena and subsequent affective alterations remains unclear. However, other authors have concluded that both categories should be taken into account as factors that would precipitate relapse. Specifically, SID has been associated with a shorter time for the first alcohol consumption after discharge, while ID, in addition, predicted relapse to alcohol dependence. Interestingly, ID prior to the AUD did not predict outcomes for patients [56].

**21**

with abstinence [62].

*Rethinking the Use of Antidepressants to Treat Alcohol Use Disorders and Depression…*

Results from clinical studies underline the need to understand possible underlying factors that contribute to the mutual negative influence of both pathologies. In this sense, animal models of AUD and depression offer the possibility of elucidating potential factors involved in the development of dual disorders [57]. Despite the prevalent comorbidity between depression and AUDs, direct evidence of causality of co-occurrence of the two pathologies is still scarce. Thus, Riga et al. [58] used a combination of models of depression and AUD through social defeat and alcohol self-administration and reported that a persistent depressive-like state led to profound alcohol reward-related changes, exaggerating the incentive salience of alcohol and facilitating cue-induced relapse to alcohol seeking. In addition, Lee et al. [47] reported higher alcohol self-administration behavior in mice which exhibited depressive-like behavior in prolonged abstinence as consequence of alcohol selfadministration. It is interesting to note that this condition only occurred in animals that were exposed to alcohol during their adolescence and not in those in which the first exposure took place during adulthood, and that did not show alcohol-related affective alterations. Animal studies would show that affective alterations that persist in prolonged abstinence, regardless of whether they were related or not with alcohol exposure, would increase self-administration behavior under alcohol

**3. Alcohol use disorders and hippocampal neurogenesis deterioration**

**3.1 Clinical evidence of AUDs contributing to hippocampal** 

Years ago, the proposal arose that alcohol abuse might exert its negative effect in the human brain through an induction of neuronal loss on the hippocampus. In agreement, animal models of chronic alcohol exposure have shown consistently that alcohol is toxic to hippocampal neurons, inducing cell loss. Subsequent studies have led to suggest that alcohol may result in hippocampal pathology and deterioration

The lack of techniques to assess adult HN in vivo in AUD patients limits the available information in this regard essentially to postmortem or neuroimaging studies. To date, we have only found one study that has shown that alcohol would have a negative effect on HN in humans [59]. Authors reported reduced numbers of three biomarkers representing different stages of the HN process: Ki67, as marker for cell proliferation, the sex determining region Y-box (Sox2) as stem/ progenitor cell marker, and doublecortin (DCX) as marker of neural maturation in the dentate gyrus in subjects with ongoing alcohol abuse. These results converge with previous findings in human with a history of drug abuse [60]. Otherwise, neuroimaging studies allow the detection that alcohol abuse could also impair hippocampal volume. Indeed, some studies have revealed decreases in hippocampal volume in AUD patients, although these changes have been shown to revert with abstinence (reviewed in [61]). There is also evidence of impairment in hippocampus-related functions as consequence of problematic alcohol consumption, effects that, similarly to those found in volumetric studies, could improve

**2.5 Preclinical evidence of depressive-like behavior contributing** 

*DOI: http://dx.doi.org/10.5772/intechopen.83743*

**to the risk of alcohol relapse**

re-exposition.

through effects on adult HN (see [6]).

**neurogenesis deterioration**

*Rethinking the Use of Antidepressants to Treat Alcohol Use Disorders and Depression… DOI: http://dx.doi.org/10.5772/intechopen.83743*

#### **2.5 Preclinical evidence of depressive-like behavior contributing to the risk of alcohol relapse**

Results from clinical studies underline the need to understand possible underlying factors that contribute to the mutual negative influence of both pathologies. In this sense, animal models of AUD and depression offer the possibility of elucidating potential factors involved in the development of dual disorders [57]. Despite the prevalent comorbidity between depression and AUDs, direct evidence of causality of co-occurrence of the two pathologies is still scarce. Thus, Riga et al. [58] used a combination of models of depression and AUD through social defeat and alcohol self-administration and reported that a persistent depressive-like state led to profound alcohol reward-related changes, exaggerating the incentive salience of alcohol and facilitating cue-induced relapse to alcohol seeking. In addition, Lee et al. [47] reported higher alcohol self-administration behavior in mice which exhibited depressive-like behavior in prolonged abstinence as consequence of alcohol selfadministration. It is interesting to note that this condition only occurred in animals that were exposed to alcohol during their adolescence and not in those in which the first exposure took place during adulthood, and that did not show alcohol-related affective alterations. Animal studies would show that affective alterations that persist in prolonged abstinence, regardless of whether they were related or not with alcohol exposure, would increase self-administration behavior under alcohol re-exposition.

#### **3. Alcohol use disorders and hippocampal neurogenesis deterioration**

Years ago, the proposal arose that alcohol abuse might exert its negative effect in the human brain through an induction of neuronal loss on the hippocampus. In agreement, animal models of chronic alcohol exposure have shown consistently that alcohol is toxic to hippocampal neurons, inducing cell loss. Subsequent studies have led to suggest that alcohol may result in hippocampal pathology and deterioration through effects on adult HN (see [6]).

#### **3.1 Clinical evidence of AUDs contributing to hippocampal neurogenesis deterioration**

The lack of techniques to assess adult HN in vivo in AUD patients limits the available information in this regard essentially to postmortem or neuroimaging studies. To date, we have only found one study that has shown that alcohol would have a negative effect on HN in humans [59]. Authors reported reduced numbers of three biomarkers representing different stages of the HN process: Ki67, as marker for cell proliferation, the sex determining region Y-box (Sox2) as stem/ progenitor cell marker, and doublecortin (DCX) as marker of neural maturation in the dentate gyrus in subjects with ongoing alcohol abuse. These results converge with previous findings in human with a history of drug abuse [60]. Otherwise, neuroimaging studies allow the detection that alcohol abuse could also impair hippocampal volume. Indeed, some studies have revealed decreases in hippocampal volume in AUD patients, although these changes have been shown to revert with abstinence (reviewed in [61]). There is also evidence of impairment in hippocampus-related functions as consequence of problematic alcohol consumption, effects that, similarly to those found in volumetric studies, could improve with abstinence [62].

*Antidepressants - Preclinical, Clinical and Translational Aspects*

in which depression manifests itself in abstinent AUD patients.

**2.4 Clinical evidence of depressive symptomatology contributing** 

Interestingly, ID prior to the AUD did not predict outcomes for patients [56].

**to the risk of alcohol relapse**

As previously mentioned, a negative affective state is not only a consequence of consumption but also could represent a maintenance factor for the addiction cycle [28]. In coherence, the "self-medication" theory postulates that the desire to avoid or alleviate preexisting or abstinence-related aversive states is a determining factor of excessive drug use and relapse [48]. Relapse is one of the most complicated components of drug addiction and involves a complex interaction of drug-associated cues that respond to multiple biological, psychiatric, psychological, and psychosocial factors which may precipitate the restoration of consumption [49, 50]. Therefore, one of the main goals in treating substance abuse is to preserve abstinence.

Clinical data strongly support the relevance of negative emotionality in protracted abstinence and relapse. Thus, for example, a higher prevalence of depressed mood has been observed in AUD patients who relapsed [51]. Depression-related low motivation has been shown to precipitate alcohol relapse, while improvements contributed to greater abstinence [52–55]. In fact, those studies have emphasized the need to treat depression to preserve abstinence and improve outcome of patients with AUD. We mentioned before that the AUD can contribute to an ID or a SID. Thus, some authors wonder whether transient symptomatology (SID) would affect consumption in the same way as the observed ID in prolonged abstinence. In this sense, it has been suggested that while affective dysregulation in protracted abstinence is likely to be of immediate relevance for relapse to excessive alcohol use, the link between the early withdrawal phenomena and subsequent affective alterations remains unclear. However, other authors have concluded that both categories should be taken into account as factors that would precipitate relapse. Specifically, SID has been associated with a shorter time for the first alcohol consumption after discharge, while ID, in addition, predicted relapse to alcohol dependence.

**2.3 Depression contributes to the risk of alcohol relapse**

allow a larger approach to the possible underlying causes in the relation of the AUD and depression. Several preclinical studies have assessed behavioral alterations during acute withdrawal and/or protracted abstinence in different animal models of alcohol abuse [36–47]. Studies used rodents as experimental animals, and the majority used the AUD model of chronic intermittent ethanol (CIE) vapor exposure. Behavioral analysis was carried out from a few hours (less than 24 hours) to several days or weeks after the last alcohol consumption, using the forced swimming test (FST) the most frequently used paradigm for this purpose. FST allows detecting responses toward an inescapable stress in animals based on the measurement of the time they remain immobile rather than displaying active strategies, akin to responses that would be impaired in depression. This response has been commonly described in the literature as depressive-like behavior. Affective alterations induced by alcohol were generally detected once alcohol exposure ceased, regardless of the animal model used, with few exceptions. It is interesting to note that studies evaluating both acute and chronic abstinence found occurrence of depressive-like behavior in both experimental periods although mostly after prolonged abstinence, which may indicate that the negative affective state as a consequence of abstinence, especially when maintained for prolonged periods, might be a risk factor for displaying depressive-like behavior, analogous to the way

**20**

#### **3.2 Preclinical evidence of alcohol contributing to hippocampal neurogenesis deterioration**

Animal studies are useful to compensate for the limited clinical evidence in AUD patients. In fact, the most consistent evidence of alcohol-induced hippocampal impairment due to, in part, its action on HN comes from preclinical studies. In addition, the different immunolabeling techniques allow us to differentiate the stages of adult animal HN, as proliferation, maturation, migration, and survival of newly generated cells. Obtaining samples throughout different stages offers detailed information on how these processes are altered along the addictive cycle, which constitutes a great advantage over the limitations of postmortem studies in humans. The majority of in vivo studies have shown that alcohol intoxication leads to an overall decrease in HN through alcohol's effects on cell proliferation and survival [63], while those HN parameters show heterogeneous results when assessed throughout abstinence. Several animal studies have evaluated HN parameters along acute withdrawal and/or protracted abstinence in different AUD models. Studies mainly analyzed parameters of HN at different times throughout abstinence and reported increases, decreases, and mixed results in HN-related parameters [64–79]. Studies were mainly in rodents (except [72], done in nonhuman primates). A large part of the studies used a 4-day binge model or self-administration protocols, whereas few authors used the CIE vapor exposure model. Different immunolabeling techniques have been used to assess HN in animals, mainly the thymidine analogue bromodeoxyuridine (BrdU), which is incorporated into dividing cells and allows monitoring of newly generated neurons in the adult brain. Main relevant aspects of results from those studies are analyzed in detail in the conclusion.

#### **3.3 Hippocampal neurogenesis deterioration contributes to the risk of alcohol relapse**

Hippocampus is essential in consolidation of stimuli previously paired with drug intake, and authors have proposed that alcohol produces strong deficits in hippocampus-dependent learning and memory and attenuates hippocampal plasticity during withdrawal, which may motivate attempts to self-medicate resulting in relapse and maintenance of drug use [80]. In this sense, one way by which impaired HN could contribute to addiction would be by disrupting learning and memory and by inducing negative affective states, both factors increasing susceptibility to relapse [81]. On the other hand, research during the last decade has shown that it is possible to disrupt alcohol-induced cues and that this has a lasting impact in reducing the tendency to seek drugs and to relapse [82]. In this regard, authors have suggested that although there are a host of plastic changes that occur with abstinence, one way that the hippocampus may recover in abstinence is through the repopulation of the dentate gyrus by adult HN [6].

#### **3.4 Clinical evidence of hippocampal neurogenesis deterioration contributes to the risk of alcohol relapse**

In the same way as in the previous sections, human studies provide indirect indicators of the role of HN, such as the volume and functionality of the hippocampus. In this regard, clinical studies found that deficits in hippocampal volume in AUD patients compared with healthy controls normalize over an abstinence period of 2 weeks [83] and that hippocampal volume did not constitute a predictive factor for relapse risk in abstinent alcoholics [84]. On the other hand, it has been observed that the hippocampal-dependent functions could continue to be altered even in prolonged abstinence [62], which could be a factor that, as other authors propose,

**23**

*Rethinking the Use of Antidepressants to Treat Alcohol Use Disorders and Depression…*

**3.5 Preclinical evidence of hippocampal neurogenesis deterioration** 

**4. AD treatment in alcohol use disorders, depression,** 

Several studies have led to the suggestion that reversing depressive symptomatology [54] and HN deterioration [21] could be a therapeutical option in cases of comorbidity between AUDs and depression. Given the potential of ADs to improve affective symptoms and promote HN, it is reasonable to assume that such treatment would benefit AUD patients. The following sections attempt to clarify these aspects.

Meta-analysis and reviews that integrate results of clinical studies in which patients with AUD and depression were treated with ADs show drug-dependent and inconclusive results. Some findings showed that SSRIs adequately treat depressive symptomatology in individuals with AUD and depression [85–87], while others showed that SSRIs were not more effective than placebo in treating comorbid patients [88, 89]. In relation, it has also been seen that SSRIs would not show greater effects than TCAs [90]. In fact, results from different studies using TCAs seem to converge in its effectiveness in alleviating depressive symptomatology [88, 91]. This may present differences in the response to a treatment for

**4.1 Clinical evidence of antidepressant treatment improves depressive symptomatology and hippocampal neurogenesis deterioration**

**and hippocampal neurogenesis**

would alter cognitive aspects linked to the risk of relapse [80]. Information from clinical studies shows that the course of the AUD would be related to the functionality of the hippocampus and not so much with alterations in its structure. Unfortunately, like the previous section, we are faced with a lack of clinical evidence in this regard, since we do not have information on the role that newly generated neurons in the hippocampus would play on the learning and memory processes

Numerous animal studies have led to suggest that low neurogenic states could regulate the addictive behavior, assuming a factor of addiction or comorbid vulnerability [12]. Specifically, animal models of drug addiction studies have led to propose that adult HN appears to be important for the maintenance of hippocampal neuroplasticity, such that reducing HN during abstinence may increase the vulnerability to relapse, while enhancing HN during abstinence may help reduce the risk of relapse [22]. Among the studies cited that assessed HN parameters, only one study [78] analyzed the levels of alcohol consumption after the period of abstinence. Thus, they reported augmented alcohol self-administration after 4 weeks of abstinence in animals that showed reduced HN at the end of the experiment as consequence of a combination of selfadministration and vapor exposures to alcohol (dependent animals) compared to animals that showed no reductions in HN who did not receive exposure to vaporized alcohol (nondependent animals). Some results from [78] suggest that the observed reactive HN effect does not have an implication in recovery. On the contrary, animals that showed this reactive effect and lower levels of survival of newly generated neurons ended up showing higher alcohol consumption during relapse. Main implications of these findings are analyzed in

*DOI: http://dx.doi.org/10.5772/intechopen.83743*

**contributes to the risk of alcohol relapse**

involved in prevent relapse.

the conclusion.

*Rethinking the Use of Antidepressants to Treat Alcohol Use Disorders and Depression… DOI: http://dx.doi.org/10.5772/intechopen.83743*

would alter cognitive aspects linked to the risk of relapse [80]. Information from clinical studies shows that the course of the AUD would be related to the functionality of the hippocampus and not so much with alterations in its structure. Unfortunately, like the previous section, we are faced with a lack of clinical evidence in this regard, since we do not have information on the role that newly generated neurons in the hippocampus would play on the learning and memory processes involved in prevent relapse.

#### **3.5 Preclinical evidence of hippocampal neurogenesis deterioration contributes to the risk of alcohol relapse**

Numerous animal studies have led to suggest that low neurogenic states could regulate the addictive behavior, assuming a factor of addiction or comorbid vulnerability [12]. Specifically, animal models of drug addiction studies have led to propose that adult HN appears to be important for the maintenance of hippocampal neuroplasticity, such that reducing HN during abstinence may increase the vulnerability to relapse, while enhancing HN during abstinence may help reduce the risk of relapse [22]. Among the studies cited that assessed HN parameters, only one study [78] analyzed the levels of alcohol consumption after the period of abstinence. Thus, they reported augmented alcohol self-administration after 4 weeks of abstinence in animals that showed reduced HN at the end of the experiment as consequence of a combination of selfadministration and vapor exposures to alcohol (dependent animals) compared to animals that showed no reductions in HN who did not receive exposure to vaporized alcohol (nondependent animals). Some results from [78] suggest that the observed reactive HN effect does not have an implication in recovery. On the contrary, animals that showed this reactive effect and lower levels of survival of newly generated neurons ended up showing higher alcohol consumption during relapse. Main implications of these findings are analyzed in the conclusion.

#### **4. AD treatment in alcohol use disorders, depression, and hippocampal neurogenesis**

Several studies have led to the suggestion that reversing depressive symptomatology [54] and HN deterioration [21] could be a therapeutical option in cases of comorbidity between AUDs and depression. Given the potential of ADs to improve affective symptoms and promote HN, it is reasonable to assume that such treatment would benefit AUD patients. The following sections attempt to clarify these aspects.

#### **4.1 Clinical evidence of antidepressant treatment improves depressive symptomatology and hippocampal neurogenesis deterioration**

Meta-analysis and reviews that integrate results of clinical studies in which patients with AUD and depression were treated with ADs show drug-dependent and inconclusive results. Some findings showed that SSRIs adequately treat depressive symptomatology in individuals with AUD and depression [85–87], while others showed that SSRIs were not more effective than placebo in treating comorbid patients [88, 89]. In relation, it has also been seen that SSRIs would not show greater effects than TCAs [90]. In fact, results from different studies using TCAs seem to converge in its effectiveness in alleviating depressive symptomatology [88, 91]. This may present differences in the response to a treatment for

*Antidepressants - Preclinical, Clinical and Translational Aspects*

**neurogenesis deterioration**

**of alcohol relapse**

**3.2 Preclinical evidence of alcohol contributing to hippocampal** 

**3.3 Hippocampal neurogenesis deterioration contributes to the risk** 

repopulation of the dentate gyrus by adult HN [6].

**contributes to the risk of alcohol relapse**

**3.4 Clinical evidence of hippocampal neurogenesis deterioration** 

In the same way as in the previous sections, human studies provide indirect indicators of the role of HN, such as the volume and functionality of the hippocampus. In this regard, clinical studies found that deficits in hippocampal volume in AUD patients compared with healthy controls normalize over an abstinence period of 2 weeks [83] and that hippocampal volume did not constitute a predictive factor for relapse risk in abstinent alcoholics [84]. On the other hand, it has been observed that the hippocampal-dependent functions could continue to be altered even in prolonged abstinence [62], which could be a factor that, as other authors propose,

Hippocampus is essential in consolidation of stimuli previously paired with drug intake, and authors have proposed that alcohol produces strong deficits in hippocampus-dependent learning and memory and attenuates hippocampal plasticity during withdrawal, which may motivate attempts to self-medicate resulting in relapse and maintenance of drug use [80]. In this sense, one way by which impaired HN could contribute to addiction would be by disrupting learning and memory and by inducing negative affective states, both factors increasing susceptibility to relapse [81]. On the other hand, research during the last decade has shown that it is possible to disrupt alcohol-induced cues and that this has a lasting impact in reducing the tendency to seek drugs and to relapse [82]. In this regard, authors have suggested that although there are a host of plastic changes that occur with abstinence, one way that the hippocampus may recover in abstinence is through the

Animal studies are useful to compensate for the limited clinical evidence in AUD patients. In fact, the most consistent evidence of alcohol-induced hippocampal impairment due to, in part, its action on HN comes from preclinical studies. In addition, the different immunolabeling techniques allow us to differentiate the stages of adult animal HN, as proliferation, maturation, migration, and survival of newly generated cells. Obtaining samples throughout different stages offers detailed information on how these processes are altered along the addictive cycle, which constitutes a great advantage over the limitations of postmortem studies in humans. The majority of in vivo studies have shown that alcohol intoxication leads to an overall decrease in HN through alcohol's effects on cell proliferation and survival [63], while those HN parameters show heterogeneous results when assessed throughout abstinence. Several animal studies have evaluated HN parameters along acute withdrawal and/or protracted abstinence in different AUD models. Studies mainly analyzed parameters of HN at different times throughout abstinence and reported increases, decreases, and mixed results in HN-related parameters [64–79]. Studies were mainly in rodents (except [72], done in nonhuman primates). A large part of the studies used a 4-day binge model or self-administration protocols, whereas few authors used the CIE vapor exposure model. Different immunolabeling techniques have been used to assess HN in animals, mainly the thymidine analogue bromodeoxyuridine (BrdU), which is incorporated into dividing cells and allows monitoring of newly generated neurons in the adult brain. Main relevant aspects of results from those studies are analyzed in detail in the conclusion.

**22**

depression in alcohol-dependent participants depending on the different types of depression, as a stronger effect of ADs was found in ID than in SID patients [32]. The most recent meta-analysis available concerning the efficacy of AD treatment in these patients shows a modest effect in some outcomes of depression [92]. However, most authors point out the need for more studies with similar outcome measures, well-defined sample designs, adequate doses, and duration of treatment so that the integration of studies can reach conclusions with a high quality of evidence [87, 90, 92], and some of them emphasize the need to evaluate possible alternative ADs, as, for example, nonselective or partial agonist-reuptake inhibitors [93, 94]. On the other hand, as seen in the introduction, ADs have shown to potentially increase HN in depressed patients [20, 21]. Unfortunately, no evidence of AD-related HN effect has been described in AUD patients.

#### **4.2 Preclinical evidence of antidepressant treatment improves depressive-like behavior and hippocampal neurogenesis deterioration in alcohol exposure and abstinence**

Studies in animals have suggested that the ability of AD treatment to affect HN would be linked to its behavioral therapeutic effects [8]. In fact, authors reported that increasing HN has been demonstrated to be necessary and sufficient to reduce depressive-like behavior in animals [95]. On the contrary, other authors have concluded that, although ADs promote HN, this would not be a critical event for their mood-rectifying actions [96]. In the same direction, authors have proposed that the therapeutic effect of the AD would not be determined exclusively by an increase in the number of newly generated neurons but rather in the way in which those neurons are functionally incorporated into hippocampal preexisting circuits that would be linked to recovery [97]. Few animal studies evaluated the efficacy of an AD treatment (desipramine, imipramine, and amitifadine) in a model of alcohol exposure. Studies from Getachew et al. [36, 43] found that subchronic desipramine and imipramine treatment reversed depression-like behavior and anxiety in rodents under acute withdrawal conditions. Similarly, Warnock et al. [39] reported that two different doses of acute amitifadine reversed the abstinence-induced increased immobility in the FST. Finally, Stevenson et al. [37] reported that subchronic desipramine reverted depression-like behavior and restored HN parameters, both aspects impaired under protracted abstinence conditions in mice. Similarly, other studies have tested the efficacy of AD-like drugs as 7,8-DHF, a trkB agonist [40]; trichostatin A, a histone deacetylase inhibitor [76]; rolipram, a phosphodiesterase-4 inhibitor [45]; or ketamine, a N-methyl-D-aspartate receptor antagonist [42, 46], reporting that those treatments also restored the HN parameters and/or the behavioral alterations impaired by the exposure and abstinence to alcohol. In addition, non-pharmacological conditions, as wheel running or natural extracts, induced similar patterns of recovery in HN parameters [65, 77] and in depressive-like behavior [45, 50] in rodents exposed and abstinent of alcohol. This data, in conjunction with previous studies that used ADs, would suggest that if a treatment had protective effects on the NH function, it could also reflect its therapeutic effect on affective disturbances in alcohol exposed animals. Nevertheless, the causality of this relationship needs to be further elucidated. **Figure 2** illustrates the possible state and role of HN during alcohol withdrawal.

#### **4.3 Clinical evidence of antidepressant treatment improves depressive and alcohol use disorder outcome**

Although ADs are not among the first-line treatment options in AUD, they are among the additional alternative treatments available, mainly when comorbid

**25**

**Figure 2.**

*neurons into neural pathways of recovery.*

*Rethinking the Use of Antidepressants to Treat Alcohol Use Disorders and Depression…*

conditions are present [16]. In this regard, authors have proposed that AD treatment could ameliorate alcohol consumption [98], possibly by improving depressive symptoms [99]. Some of the aforementioned studies and meta-analysis evaluated alcohol-related outcomes in AUD depressed patients [87, 90, 92], showing a modest or no efficacy of AD treatment in alleviating some aspects linked to alcohol consumption. Recent conclusions show that ADs increased the number of participants abstaining during the trials and reduced the number of drinks per drinking day, while no differences were reported between ADs and placebo in other relevant outcomes of the AUD [92]. In addition to the mentioned low overall effectiveness, it is important to mention that some studies reported even poorer drinking outcomes in AUD patients treated with SSRIs compared to those treated with placebo [100–102]. In this line, studies have reported clinical cases where treatment with SSRIs appears to be the cause of increased frequency of intoxication by alcohol and new onset of alcohol-related problems [103–105]. Finally, patients who actively drink suffering of comorbid anxiety and AUD have also shown that they may increase alcohol con-

*(a) Schematic representation of the adult HN along alcohol withdrawal and abstinence. Spontaneous burst in cell proliferation is followed by a lower survivability and aberrant patterns of cell migration and integration of the newly generated neurons which could contribute to vulnerability related circuitry. (b) Exogenously induced cell proliferation (by physical exercise or proneurogenic treatment as ADs) could prevent the consolidation of neural circuitry involved in vulnerability, promoting survivability and integration of the newly generated* 

**4.4 Preclinical evidence of antidepressant treatment improves alcohol relapse**

Preclinical data concerning the effectiveness of pharmacological treatments in AUDs is still scarce [107]. Animal studies that evaluate the effect of different AD treatments on preventing alcohol consumption report reduction in alcohol intake after an acute drug dose or under short-term relapse conditions [108]. Nonetheless, taking in mind that the evaluation of the effectiveness of conventional AD treatment should be done considering the delay in its therapeutic effects, studies should go beyond short-term evaluations, assessing long-term

sumption under treatment with SSRIs [106].

*DOI: http://dx.doi.org/10.5772/intechopen.83743*

*Rethinking the Use of Antidepressants to Treat Alcohol Use Disorders and Depression… DOI: http://dx.doi.org/10.5772/intechopen.83743*

#### **Figure 2.**

*Antidepressants - Preclinical, Clinical and Translational Aspects*

of AD-related HN effect has been described in AUD patients.

**in alcohol exposure and abstinence**

possible state and role of HN during alcohol withdrawal.

**and alcohol use disorder outcome**

**4.3 Clinical evidence of antidepressant treatment improves depressive** 

Although ADs are not among the first-line treatment options in AUD, they are among the additional alternative treatments available, mainly when comorbid

**4.2 Preclinical evidence of antidepressant treatment improves** 

**depressive-like behavior and hippocampal neurogenesis deterioration** 

Studies in animals have suggested that the ability of AD treatment to affect HN would be linked to its behavioral therapeutic effects [8]. In fact, authors reported that increasing HN has been demonstrated to be necessary and sufficient to reduce depressive-like behavior in animals [95]. On the contrary, other authors have concluded that, although ADs promote HN, this would not be a critical event for their mood-rectifying actions [96]. In the same direction, authors have proposed that the therapeutic effect of the AD would not be determined exclusively by an increase in the number of newly generated neurons but rather in the way in which those neurons are functionally incorporated into hippocampal preexisting circuits that would be linked to recovery [97]. Few animal studies evaluated the efficacy of an AD treatment (desipramine, imipramine, and amitifadine) in a model of alcohol exposure. Studies from Getachew et al. [36, 43] found that subchronic desipramine and imipramine treatment reversed depression-like behavior and anxiety in rodents under acute withdrawal conditions. Similarly, Warnock et al. [39] reported that two different doses of acute amitifadine reversed the abstinence-induced increased immobility in the FST. Finally, Stevenson et al. [37] reported that subchronic desipramine reverted depression-like behavior and restored HN parameters, both aspects impaired under protracted abstinence conditions in mice. Similarly, other studies have tested the efficacy of AD-like drugs as 7,8-DHF, a trkB agonist [40]; trichostatin A, a histone deacetylase inhibitor [76]; rolipram, a phosphodiesterase-4 inhibitor [45]; or ketamine, a N-methyl-D-aspartate receptor antagonist [42, 46], reporting that those treatments also restored the HN parameters and/or the behavioral alterations impaired by the exposure and abstinence to alcohol. In addition, non-pharmacological conditions, as wheel running or natural extracts, induced similar patterns of recovery in HN parameters [65, 77] and in depressive-like behavior [45, 50] in rodents exposed and abstinent of alcohol. This data, in conjunction with previous studies that used ADs, would suggest that if a treatment had protective effects on the NH function, it could also reflect its therapeutic effect on affective disturbances in alcohol exposed animals. Nevertheless, the causality of this relationship needs to be further elucidated. **Figure 2** illustrates the

depression in alcohol-dependent participants depending on the different types of depression, as a stronger effect of ADs was found in ID than in SID patients [32]. The most recent meta-analysis available concerning the efficacy of AD treatment in these patients shows a modest effect in some outcomes of depression [92]. However, most authors point out the need for more studies with similar outcome measures, well-defined sample designs, adequate doses, and duration of treatment so that the integration of studies can reach conclusions with a high quality of evidence [87, 90, 92], and some of them emphasize the need to evaluate possible alternative ADs, as, for example, nonselective or partial agonist-reuptake inhibitors [93, 94]. On the other hand, as seen in the introduction, ADs have shown to potentially increase HN in depressed patients [20, 21]. Unfortunately, no evidence

**24**

*(a) Schematic representation of the adult HN along alcohol withdrawal and abstinence. Spontaneous burst in cell proliferation is followed by a lower survivability and aberrant patterns of cell migration and integration of the newly generated neurons which could contribute to vulnerability related circuitry. (b) Exogenously induced cell proliferation (by physical exercise or proneurogenic treatment as ADs) could prevent the consolidation of neural circuitry involved in vulnerability, promoting survivability and integration of the newly generated neurons into neural pathways of recovery.*

conditions are present [16]. In this regard, authors have proposed that AD treatment could ameliorate alcohol consumption [98], possibly by improving depressive symptoms [99]. Some of the aforementioned studies and meta-analysis evaluated alcohol-related outcomes in AUD depressed patients [87, 90, 92], showing a modest or no efficacy of AD treatment in alleviating some aspects linked to alcohol consumption. Recent conclusions show that ADs increased the number of participants abstaining during the trials and reduced the number of drinks per drinking day, while no differences were reported between ADs and placebo in other relevant outcomes of the AUD [92]. In addition to the mentioned low overall effectiveness, it is important to mention that some studies reported even poorer drinking outcomes in AUD patients treated with SSRIs compared to those treated with placebo [100–102]. In this line, studies have reported clinical cases where treatment with SSRIs appears to be the cause of increased frequency of intoxication by alcohol and new onset of alcohol-related problems [103–105]. Finally, patients who actively drink suffering of comorbid anxiety and AUD have also shown that they may increase alcohol consumption under treatment with SSRIs [106].

#### **4.4 Preclinical evidence of antidepressant treatment improves alcohol relapse**

Preclinical data concerning the effectiveness of pharmacological treatments in AUDs is still scarce [107]. Animal studies that evaluate the effect of different AD treatments on preventing alcohol consumption report reduction in alcohol intake after an acute drug dose or under short-term relapse conditions [108]. Nonetheless, taking in mind that the evaluation of the effectiveness of conventional AD treatment should be done considering the delay in its therapeutic effects, studies should go beyond short-term evaluations, assessing long-term

consequences of treatment in animal models that better mimic AUD patient conditions [109]. Thus, unlike studies using acute treatments, authors that evaluated chronic and subchronic escitalopram, sertraline, paroxetine, fluoxetine (SSRIs), and duloxetine, dual serotonin/norepinephrine reuptake inhibitor (SNRI) treatments found that, along the treatment period, animals showed lower alcohol intake levels, but cessation of treatment produced a restoration of basal alcohol consumption [110–112]. Ho et al. [110] also found an augmentation in alcohol intake in depressed animals once treatment with escitalopram ceased. Interestingly, authors also found the same effect in animals under combination of AD (escitalopram) and anti-relapse (acamprosate) treatments. Related to that, subchronic treatment with different ADs (SSRIs and SNRIs) has been demonstrated to augment alcohol consumption in animal models of alcohol deprivation, which were treated along abstinence and re-exposed to alcohol selfadministration once AD treatment ended [113, 114].

#### **5. Conclusions**

Translating evidence from preclinical studies to clinical practice still creates a major challenge in development of new pharmacological treatments in AUDs. The first thing we must point out is the lack of animal studies that have evaluated the effectiveness of the AD treatment in alcohol exposure and abstinence. In this sense, it is important to highlight the numerous studies in animals that evaluate the alcohol exposure and abstinence impact on affective and HN parameters compared to the scarce studies that try to reverse such effects by testing appropriate ADs. In addition, strong criteria are needed when evaluating treatments in AUD animal models, highlighting the use of self-administration procedures and the evaluation of dependence by observing abstinence and relapse behavior. In this sense, animal studies evaluating HN alterations were mainly used as short periods (4 days) of forced alcohol exposition, while prolonged self-administration or CIE models, which better represent important aspects of alcohol consumption patterns in AUD patients, were used to a lesser extent.

One of the most direct methodological limitations when comparing clinical and preclinical studies is determined by the period in which the AD treatment begins. Preclinical studies would indicate that animals can display different affective responses to ADs according to the moment it is administered. In addition, AD cessation could have negative repercussions in alcohol consumption and relapse. While these effects should be further clarified in future studies, clinical trials should take these relevant aspects into account.

The debate about the implication of the new neurons generated in the hippocampus as a consequence of alcohol abstinence continues to be an object of interest. Despite alcohol-induced HN impairments that mainly persist along abstinence, some studies have shown increases in parameters of neural proliferation in animals mainly along early withdrawal periods. First, the possible role of this HN reestablishment effect as factor of recovery was considered, but later studies would even point to opposing hypotheses. In this regard, other findings led to the question whether neurons born during this reactive neurogenic process survive or properly integrate into the existing hippocampal circuitry to provide beneficial effects on hippocampal function and recovery. An early increase in neuronal proliferation induced by abstinence, followed by a reduction in survival in prolonged abstinence, appears to result in an increase in alcohol self-administration. Thus, this apparent AD-induced dual role of HN and the consequent changes in addictive behavior should be elucidated.

**27**

provided the original work is properly cited.

Raquel Gómez de Heras and Laura Orio\*

\*Address all correspondence to: lorio@psi.ucm.es

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Department of Psychobiology and Methods in Behavioral Sciences, Faculty of

Antonio Ballesta, Francisco Alén, Fernando Rodríguez de Fonseca,

Psychology, Complutense University of Madrid, Madrid, Spain

*Rethinking the Use of Antidepressants to Treat Alcohol Use Disorders and Depression…*

To resume, preclinical evidence strongly supports that alcohol consumption and abstinence lead to negative affective states and alterations in HN, some of which may persist in prolonged abstinence. Although affective alterations related to alcohol have been evaluated, there is limited data available concerning the alcoholinduced HN deterioration in clinical patients. Both alcohol-induced depression and changes in HN could be relevant to promote relapse, exacerbating the addictive cycle, although additional studies should clarify this complex interaction. Conventional ADs have been proposed to alleviate affective alterations possibly by promoting HN; thus AUD depressed patients could benefit from its effects. Unfortunately, clinical trials still face several limitations in order to draw reliable conclusions in this regard. Moreover, preclinical studies should bear in mind important methodological aspects onward when translating information regarding

The authors are grateful to funding support from Plan Nacional Sobre Drogas (PNSD), ref: 2015/005 to L.O. (Ministerio de Sanidad, Política Social e Igualdad).

*DOI: http://dx.doi.org/10.5772/intechopen.83743*

the efficacy of AD treatment into AUD patients.

The authors declare no conflict of interest.

**Acknowledgements**

**Conflict of interest**

**Author details**

*Rethinking the Use of Antidepressants to Treat Alcohol Use Disorders and Depression… DOI: http://dx.doi.org/10.5772/intechopen.83743*

To resume, preclinical evidence strongly supports that alcohol consumption and abstinence lead to negative affective states and alterations in HN, some of which may persist in prolonged abstinence. Although affective alterations related to alcohol have been evaluated, there is limited data available concerning the alcoholinduced HN deterioration in clinical patients. Both alcohol-induced depression and changes in HN could be relevant to promote relapse, exacerbating the addictive cycle, although additional studies should clarify this complex interaction. Conventional ADs have been proposed to alleviate affective alterations possibly by promoting HN; thus AUD depressed patients could benefit from its effects. Unfortunately, clinical trials still face several limitations in order to draw reliable conclusions in this regard. Moreover, preclinical studies should bear in mind important methodological aspects onward when translating information regarding the efficacy of AD treatment into AUD patients.

#### **Acknowledgements**

*Antidepressants - Preclinical, Clinical and Translational Aspects*

administration once AD treatment ended [113, 114].

**5. Conclusions**

patients, were used to a lesser extent.

these relevant aspects into account.

consequences of treatment in animal models that better mimic AUD patient conditions [109]. Thus, unlike studies using acute treatments, authors that evaluated chronic and subchronic escitalopram, sertraline, paroxetine, fluoxetine (SSRIs), and duloxetine, dual serotonin/norepinephrine reuptake inhibitor (SNRI) treatments found that, along the treatment period, animals showed lower alcohol intake levels, but cessation of treatment produced a restoration of basal alcohol consumption [110–112]. Ho et al. [110] also found an augmentation in alcohol intake in depressed animals once treatment with escitalopram ceased. Interestingly, authors also found the same effect in animals under combination of AD (escitalopram) and anti-relapse (acamprosate) treatments. Related to that, subchronic treatment with different ADs (SSRIs and SNRIs) has been demonstrated to augment alcohol consumption in animal models of alcohol deprivation, which were treated along abstinence and re-exposed to alcohol self-

Translating evidence from preclinical studies to clinical practice still creates a major challenge in development of new pharmacological treatments in AUDs. The first thing we must point out is the lack of animal studies that have evaluated the effectiveness of the AD treatment in alcohol exposure and abstinence. In this sense, it is important to highlight the numerous studies in animals that evaluate the alcohol exposure and abstinence impact on affective and HN parameters compared to the scarce studies that try to reverse such effects by testing appropriate ADs. In addition, strong criteria are needed when evaluating treatments in AUD animal models, highlighting the use of self-administration procedures and the evaluation of dependence by observing abstinence and relapse behavior. In this sense, animal studies evaluating HN alterations were mainly used as short periods (4 days) of forced alcohol exposition, while prolonged self-administration or CIE models, which better represent important aspects of alcohol consumption patterns in AUD

One of the most direct methodological limitations when comparing clinical and preclinical studies is determined by the period in which the AD treatment begins. Preclinical studies would indicate that animals can display different affective responses to ADs according to the moment it is administered. In addition, AD cessation could have negative repercussions in alcohol consumption and relapse. While these effects should be further clarified in future studies, clinical trials should take

The debate about the implication of the new neurons generated in the hippocampus as a consequence of alcohol abstinence continues to be an object of interest. Despite alcohol-induced HN impairments that mainly persist along abstinence, some studies have shown increases in parameters of neural proliferation in animals mainly along early withdrawal periods. First, the possible role of this HN reestablishment effect as factor of recovery was considered, but later studies would even point to opposing hypotheses. In this regard, other findings led to the question whether neurons born during this reactive neurogenic process survive or properly integrate into the existing hippocampal circuitry to provide beneficial effects on hippocampal function and recovery. An early increase in neuronal proliferation induced by abstinence, followed by a reduction in survival in prolonged abstinence, appears to result in an increase in alcohol self-administration. Thus, this apparent AD-induced dual role of HN and the consequent changes in addictive behavior

**26**

should be elucidated.

The authors are grateful to funding support from Plan Nacional Sobre Drogas (PNSD), ref: 2015/005 to L.O. (Ministerio de Sanidad, Política Social e Igualdad).

#### **Conflict of interest**

The authors declare no conflict of interest.

#### **Author details**

Antonio Ballesta, Francisco Alén, Fernando Rodríguez de Fonseca, Raquel Gómez de Heras and Laura Orio\* Department of Psychobiology and Methods in Behavioral Sciences, Faculty of Psychology, Complutense University of Madrid, Madrid, Spain

\*Address all correspondence to: lorio@psi.ucm.es

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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**32**

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[79] Liu W, Crews FT. Persistent decreases in adult subventricular and hippocampal neurogenesis following adolescent intermittent ethanol exposure. Frontiers in Behavioral Neuroscience. 2017;**11**:151. DOI: 10.3389/fnbeh.2017.00151

[80] Kutlu MG, Gould TJ. Effects of drugs of abuse on hippocampal plasticity and hippocampus-dependent learning and memory: Contributions to development and maintenance of addiction. Learning & Memory. 2016;**23**(10):515-533. DOI: 10.1101/ lm.042192.116

[81] Canales JJ. Deficient plasticity in the hippocampus and the spiral of addiction: Focus on adult neurogenesis. Current Topics in Behavioral Neurosciences. 2013;**15**:293-312. DOI: 10.1007/7854\_2012\_230

[82] Cui C, Noronha A, Warren K, Koob GF, Sinha R, Thakkar M, et al. Brain pathways to recovery from alcohol dependence. Alcohol (Fayetteville, N.Y.). 2015;**49**(5):435-452. DOI: 10.1016/j.alcohol.2015.04.006

[83] Kühn S, Charlet K, Schubert F, Kiefer F, Zimmermann P, Heinz A, et al. Plasticity of hippocampal subfield volume cornu ammonis 2+3 over the course of withdrawal in patients with alcohol dependence. JAMA Psychiatry. 2014;**71**(7):806-811. DOI: 10.1001/ jamapsychiatry.2014.352

[84] Gross CM, Spiegelhalder K, Mercak J, Feige B, Langosch JM. Predictability of alcohol relapse by hippocampal volumetry and psychometric variables. Psychiatry Research. 2013;**212**(1):14-18. DOI: 10.1016/j.pscychresns.2012.09.011

[85] Danovitch I, Steiner AJ, Kazdan A, Goldenberg M, Haglund M, Mirocha J, et al. Analysis of patient-reported outcomes of quality of life and functioning before and after treatment of major depressive disorder comorbid with alcohol use disorders. Journal of Addiction Medicine. 2017;**11**(1):47-54. DOI: 10.1097/adm.0000000000000268

[86] Davis LL, Wisniewski SR, Howland RH, Trivedi MH, Husain MM, Fava M, et al. Does comorbid substance use disorder impair recovery from major depression with SSRI treatment? An analysis of the STAR\*D level one treatment outcomes. Drug and Alcohol Dependence. 2010;**107**(2-3):161-170. DOI: 10.1016/j.drugalcdep.2009.10.003

[87] Nunes EV, Levin FR. Treatment of depression in patients with alcohol or other drug dependence: A meta-analysis. JAMA. 2004;**291**(15):1887-1896. DOI: 10.1001/jama.291.15.1887

[88] Iovieno N, Tedeschini E, Bentley KH, Evins AE, Papakostas GI. Antidepressants for major depressive disorder and dysthymic disorder in patients with comorbid alcohol use disorders: A meta-analysis of placebo-controlled randomized trials. The Journal of Clinical Psychiatry. 2011;**72**(8):1144-1151. DOI: 10.4088/ JCP.10m06217

[89] Zhou X, Qin B, Del Giovane C, Pan J, Gentile S, Liu Y, et al. Efficacy and tolerability of antidepressants in the treatment of adolescents and young adults with depression and substance use disorders: A systematic review and meta-analysis. Addiction. 2015;**110**(1):38-48. DOI: 10.1111/ add.12698.10

[90] Torrens M, Fonseca F, Mateu G, Farré M. Efficacy of antidepressants in substance use disorders with and without comorbid depression. A systematic review and meta-analysis. Drug and Alcohol Dependence.

**35**

*Rethinking the Use of Antidepressants to Treat Alcohol Use Disorders and Depression…*

behavior depends on hippocampal neurogenesis. Translational Psychiatry.

2013;**3**(1):e210. DOI: 10.1038/

[98] Graham K, Massak A. Alcohol consumption and the use of antidepressants. CMAJ. 2007;**176**(5):633-637. DOI: 10.1503/

[99] Mann K. Pharmacotherapy of alcohol dependence: A review of the clinical data. CNS Drugs. 2004;**18**(8):485-504. DOI: 10.2165/00023210-200418080-

[100] Charney DA, Heath LM, Zikos E, Palacios-Boix J, Gill KJ. Poorer drinking outcomes with citalopram treatment for alcohol dependence: A randomized, double-blind, placebo-controlled trial. Alcoholism, Clinical and Experimental Research. 2015;**39**(9):1756-1765. DOI:

tp.2012.141

cmaj.060446

00002

10.1111/acer.12802

[101] Chick J, Aschauer H,

drugalcdep.2003.11.012

6 months after serotonergic pharmacotherapy. Alcoholism: Clinical and Experimental Research. 2004;**28**:1065-1073. DOI: 10.1097/01.

alc.0000130974.50563.04

10.3233/JRS-130586

Hornik K. Efficacy of fluvoxamine in preventing relapse in alcohol dependence: A one-year, doubleblind, placebo-controlled multicentre study with analysis by typology. Drug and Alcohol Dependence. 2004;**74**(1):61-70. DOI: 10.1016/j.

[102] Dundon W, Lynch KG, Pettinati HM, Lipkin C. Treatment outcomes in type A and B alcohol dependence

[103] Atigari OV, Kelly AM, Jabeen Q, Healy D. New onset alcohol dependence linked to treatment with selective serotonin reuptake inhibitors. The International Journal of Risk & Safety in Medicine. 2013;**25**(105-109). DOI:

*DOI: http://dx.doi.org/10.5772/intechopen.83743*

[91] Cornelius J, Chung T, Douaihy A, Kirisci L, Glance J, Kmiec J, et al. A review of the literature of mirtazapine in co-occurring depression and an alcohol use disorder. Journal of Addictive Behaviors, Therapy & Rehabilitation. 2016;**5**(4):159. DOI:

2005;**78**(1):1-22. DOI: 10.1016/j. drugalcdep.2004.09.004

10.4172/2324-9005.1000159

[92] Agabio R, Trogu E, Pani PP. Antidepressants for the treatment of people with co-occurring depression and alcohol dependence. Cochrane Database of Systematic Reviews. 2018;**4**. Art. No.: CD008581. DOI: 10.1002/14651858.CD008581.pub2

[93] Nunes EV, Levin FR. Treatment of co-occurring depression and substance dependence: Using meta-analysis to guide clinical recommendations. Psychiatric Annals. 2008;**38**(11)

[94] Belmer A, Patkar OL, Pitman KM, Bartlett SE. Serotonergic neuroplasticity in alcohol addiction. Brain Plasticity. 2016;**1**(2):177-206. DOI: 10.3233/

[95] Hill AS, Sahay A, Hen R. Increasing adult hippocampal neurogenesis is sufficient to reduce anxiety and depression-like behaviors. Neuropsychopharmacology.

2015;**40**(10):2368-2378. DOI: 10.1038/

[96] Bessa JM, Ferreira D, Melo I, Marques F, Cerqueira JJ, Palha JA, et al. The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling. Molecular Psychiatry. 2009;**14**(8):764-773. DOI:

BPL-150022

npp.2015.85

10.1038/mp.2008.119

[97] Mateus-Pinheiro A, Pinto L, Bessa JM, Morais M, Alves ND, Monteiro S, et al. Sustained remission from depressive-like

*Rethinking the Use of Antidepressants to Treat Alcohol Use Disorders and Depression… DOI: http://dx.doi.org/10.5772/intechopen.83743*

2005;**78**(1):1-22. DOI: 10.1016/j. drugalcdep.2004.09.004

*Antidepressants - Preclinical, Clinical and Translational Aspects*

[85] Danovitch I, Steiner AJ, Kazdan A, Goldenberg M, Haglund M, Mirocha J, et al. Analysis of patient-reported outcomes of quality of life and

functioning before and after treatment of major depressive disorder comorbid with alcohol use disorders. Journal of Addiction Medicine. 2017;**11**(1):47-54. DOI: 10.1097/adm.0000000000000268

[86] Davis LL, Wisniewski SR, Howland RH, Trivedi MH, Husain MM, Fava M, et al. Does comorbid substance use disorder impair recovery from major depression with SSRI treatment? An analysis of the STAR\*D level one treatment outcomes. Drug and Alcohol Dependence. 2010;**107**(2-3):161-170. DOI: 10.1016/j.drugalcdep.2009.10.003

[87] Nunes EV, Levin FR. Treatment of depression in patients with alcohol or other drug dependence: A meta-analysis.

JAMA. 2004;**291**(15):1887-1896. DOI: 10.1001/jama.291.15.1887

[88] Iovieno N, Tedeschini E, Bentley KH, Evins AE, Papakostas GI. Antidepressants for major depressive disorder and dysthymic disorder in patients with comorbid alcohol use disorders: A meta-analysis of placebo-controlled randomized trials. The Journal of Clinical Psychiatry. 2011;**72**(8):1144-1151. DOI: 10.4088/

[89] Zhou X, Qin B, Del Giovane C, Pan J, Gentile S, Liu Y, et al. Efficacy and tolerability of antidepressants in the treatment of adolescents and young adults with depression and substance use disorders: A systematic review and meta-analysis. Addiction. 2015;**110**(1):38-48. DOI: 10.1111/

[90] Torrens M, Fonseca F, Mateu G, Farré M. Efficacy of antidepressants in substance use disorders with and without comorbid depression. A systematic review and meta-analysis. Drug and Alcohol Dependence.

JCP.10m06217

add.12698.10

dependence-induced regulation of the proliferation and survival of adult brain progenitors is associated with altered BDNF-TrkB signaling. Brain Structure & Function. 2016;**221**(9):4319-4335. DOI: 10.1007/s00429-015-1163-z

[79] Liu W, Crews FT. Persistent decreases in adult subventricular and hippocampal neurogenesis following adolescent intermittent ethanol exposure. Frontiers in Behavioral Neuroscience. 2017;**11**:151. DOI: 10.3389/fnbeh.2017.00151

[80] Kutlu MG, Gould TJ. Effects of drugs of abuse on hippocampal plasticity and hippocampus-dependent learning and memory: Contributions to development and maintenance of addiction. Learning & Memory. 2016;**23**(10):515-533. DOI: 10.1101/

[81] Canales JJ. Deficient plasticity in the hippocampus and the spiral of addiction: Focus on adult neurogenesis.

Neurosciences. 2013;**15**:293-312. DOI:

[82] Cui C, Noronha A, Warren K, Koob GF, Sinha R, Thakkar M, et al. Brain pathways to recovery from alcohol dependence. Alcohol (Fayetteville, N.Y.). 2015;**49**(5):435-452. DOI: 10.1016/j.alcohol.2015.04.006

[83] Kühn S, Charlet K, Schubert F, Kiefer F, Zimmermann P, Heinz A, et al. Plasticity of hippocampal subfield volume cornu ammonis 2+3 over the course of withdrawal in patients with alcohol dependence. JAMA Psychiatry. 2014;**71**(7):806-811. DOI: 10.1001/

[84] Gross CM, Spiegelhalder K, Mercak J, Feige B, Langosch JM. Predictability of alcohol relapse by hippocampal volumetry and psychometric variables. Psychiatry Research. 2013;**212**(1):14-18. DOI: 10.1016/j.pscychresns.2012.09.011

jamapsychiatry.2014.352

Current Topics in Behavioral

10.1007/7854\_2012\_230

lm.042192.116

**34**

[91] Cornelius J, Chung T, Douaihy A, Kirisci L, Glance J, Kmiec J, et al. A review of the literature of mirtazapine in co-occurring depression and an alcohol use disorder. Journal of Addictive Behaviors, Therapy & Rehabilitation. 2016;**5**(4):159. DOI: 10.4172/2324-9005.1000159

[92] Agabio R, Trogu E, Pani PP. Antidepressants for the treatment of people with co-occurring depression and alcohol dependence. Cochrane Database of Systematic Reviews. 2018;**4**. Art. No.: CD008581. DOI: 10.1002/14651858.CD008581.pub2

[93] Nunes EV, Levin FR. Treatment of co-occurring depression and substance dependence: Using meta-analysis to guide clinical recommendations. Psychiatric Annals. 2008;**38**(11)

[94] Belmer A, Patkar OL, Pitman KM, Bartlett SE. Serotonergic neuroplasticity in alcohol addiction. Brain Plasticity. 2016;**1**(2):177-206. DOI: 10.3233/ BPL-150022

[95] Hill AS, Sahay A, Hen R. Increasing adult hippocampal neurogenesis is sufficient to reduce anxiety and depression-like behaviors. Neuropsychopharmacology. 2015;**40**(10):2368-2378. DOI: 10.1038/ npp.2015.85

[96] Bessa JM, Ferreira D, Melo I, Marques F, Cerqueira JJ, Palha JA, et al. The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling. Molecular Psychiatry. 2009;**14**(8):764-773. DOI: 10.1038/mp.2008.119

[97] Mateus-Pinheiro A, Pinto L, Bessa JM, Morais M, Alves ND, Monteiro S, et al. Sustained remission from depressive-like

behavior depends on hippocampal neurogenesis. Translational Psychiatry. 2013;**3**(1):e210. DOI: 10.1038/ tp.2012.141

[98] Graham K, Massak A. Alcohol consumption and the use of antidepressants. CMAJ. 2007;**176**(5):633-637. DOI: 10.1503/ cmaj.060446

[99] Mann K. Pharmacotherapy of alcohol dependence: A review of the clinical data. CNS Drugs. 2004;**18**(8):485-504. DOI: 10.2165/00023210-200418080- 00002

[100] Charney DA, Heath LM, Zikos E, Palacios-Boix J, Gill KJ. Poorer drinking outcomes with citalopram treatment for alcohol dependence: A randomized, double-blind, placebo-controlled trial. Alcoholism, Clinical and Experimental Research. 2015;**39**(9):1756-1765. DOI: 10.1111/acer.12802

[101] Chick J, Aschauer H, Hornik K. Efficacy of fluvoxamine in preventing relapse in alcohol dependence: A one-year, doubleblind, placebo-controlled multicentre study with analysis by typology. Drug and Alcohol Dependence. 2004;**74**(1):61-70. DOI: 10.1016/j. drugalcdep.2003.11.012

[102] Dundon W, Lynch KG, Pettinati HM, Lipkin C. Treatment outcomes in type A and B alcohol dependence 6 months after serotonergic pharmacotherapy. Alcoholism: Clinical and Experimental Research. 2004;**28**:1065-1073. DOI: 10.1097/01. alc.0000130974.50563.04

[103] Atigari OV, Kelly AM, Jabeen Q, Healy D. New onset alcohol dependence linked to treatment with selective serotonin reuptake inhibitors. The International Journal of Risk & Safety in Medicine. 2013;**25**(105-109). DOI: 10.3233/JRS-130586

[104] Brookwell L, Hogana C, Healya D, Manginb D. Ninety-three cases of alcohol dependence following SSRI treatment. The International Journal of Risk & Safety in Medicine. 2014;**26**: 99-107. DOI: 10.3233/JRS-140616

[105] Menkes DB, Herxheimer A. Interaction between antidepressants and alcohol: Signal amplification by multiple case reports. The International Journal of Risk & Safety in Medicine. 2014;**26**(3):163-170. DOI: 10.3233/ JRS-140632

[106] Gimeno C, Dorado ML, Roncero C, Szerman N, Vega P, Balanzá-Martínez V, et al. Treatment of comorbid alcohol dependence and anxiety disorder: Review of the scientific evidence and recommendations for treatment. Frontiers in Psychiatry. 2017;**8**:173. DOI: 10.3389/fpsyt.2017.00173

[107] Barajaz AM, Kliethermes CL. An assessment of the utilization of the preclinical rodent model literature in clinical trials of putative therapeutics for the treatment of alcohol use disorders. Drug and Alcohol Dependence. 2017;**181**:77-84. DOI: 10.1016/j.drugalcdep.2017.09.022

[108] Simon O'Brien E, Legastelois R, Houchi H, Vilpoux C, Alaux-Cantin S, Pierrefiche O, et al. Fluoxetine, desipramine, and the dual antidepressant milnacipran reduce alcohol self-administration and/or relapse in dependent rats. Neuropsychopharmacology. 2011;**36**: 1518-1530. DOI: 10.1038/npp.2011.37

[109] Bell RL, Hauser SR, Liang T, Sari Y, Maldonado-Devincci A, Rodd ZA. Rat animal models for screening medications to treat alcohol use disorders. Neuropharmacology. 2017;**122**:201-243. DOI: 10.1016/j. neuropharm.2017.02.004

[110] Ho AMC, Qiu Y, Jia YF, Aguiar FS, Hinton DJ, Karpyak VM, et al.

Combined effects of acamprosate and escitalopram on ethanol consumption in mice. Alcoholism, Clinical and Experimental Research. 2016;**40**(7):1531-1539. DOI: 10.1111/ acer.13099

[111] Gulley JM, McNamara C, Barbera TJ, Ritz MC, George FR. Selective serotonin reuptake inhibitors: Effects of chronic treatment on ethanol-reinforced behavior in mice. Alcohol. 1995;**12**(3):177-181. DOI: 10.1016/0741-8329(94)00079-s

[112] Skelly MJ, Weiner JL. Chronic treatment with prazosin or duloxetine lessens concurrent anxiety-like behavior and alcohol intake: Evidence of disrupted noradrenergic signaling in anxiety-related alcohol use. Brain and Behavior. 2014;**4**(4):468-483. DOI: 10.1002/brb3.230

[113] Alén F, Orio L, Gorriti MA, de Heras RG, Ramírez-López MT, Pozo MA, et al. Increased alcohol consumption in rats after subchronic antidepressant treatment. The International Journal of Neuropsychopharmacology. 2013;**16**:1809-1818. DOI: 10.1017/ s1461145713000217

[114] Alén F, Serrano A, Gorriti MÁ, Pavón FJ, Orio L, de Heras RG, et al. The administration of atomoxetine during alcohol deprivation induces a timelimited increase in alcohol consumption after relapse. The International Journal of Neuropsychopharmacology. 2014;**17**(11):1905-1910. DOI: 10.1017/ s146114571400087x

**37**

**Chapter 3**

**Abstract**

*Jose Alfonso Ontiveros*

antidepressants, review

**1. Introduction**

Resistant Depression

Finally, some relevant neurobiological data are reviewed.

treatment options for groups of TRD patients.

**Keywords:** treatment, major depressive disorder, resistant depression,

The term "resistant" is widely employed in medical practice to point out a clinical phenomenon in which there is a lack of response to one or more therapeutic interventions. The presence of treatment resistance implies a specific series of clinical interventions, typically multidisciplinary, and focuses on solving or minimizing a medical problem. Resistance to major depressive disorder treatment, but also to other depressive disorders, such as dysthymia and bipolar depression, causes distress to patients and their relatives, and increases the number of hospital admissions, outpatient consultations, the use of psychoactive drugs, and treatment costs up to six times [1]. The definition of treatment resistant depression (TRD) continues to be ambiguous and controversial despite its serious medical and psychosocial implications. In medical literature, we can find more than 10 different definitions [2]. Many authors have published staging systems with their own definitions, descriptions, and characteristics on TRD [3–7]. The most accepted definition is a lack of response to two different pharmacological classes of antidepressants [8]. However, this definition may seem simplistic today as published treatment results on TRD patients emerge. The lack of an agreed TRD definition as well as the difficulties to do research on the subject limit our practical knowledge on the best

We review the concept and definitions of TRD. We also review the medical literature on different treatment methods studied as well as comparative studies.

Finally, we review some relevant emerging neurobiological data.

The term resistant points out a clinical phenomenon in which there is a lack of response to one or more therapeutic interventions. Resistance to major depressive disorder treatment causes distress to patients and their relatives, and increases the number of hospital admissions, outpatient consultations, use of psychoactive drugs, and treatment costs. Despite its serious medical and psychosocial medical implications, the definition of treatment resistant depression continues to be ambiguous and controversial. The lack of an agreement on definition, as well as the research on the subject being difficult, limits the practical knowledge on the best treatment options for groups of treatment resistant depression (TRD) patients. We review the concept and definitions of treatment resistant depression as well as the medical literature on different treatment methods studied and comparative studies.

## **Chapter 3** Resistant Depression

*Jose Alfonso Ontiveros*

#### **Abstract**

*Antidepressants - Preclinical, Clinical and Translational Aspects*

Combined effects of acamprosate and escitalopram on ethanol consumption in mice. Alcoholism, Clinical and Experimental Research. 2016;**40**(7):1531-1539. DOI: 10.1111/

[111] Gulley JM, McNamara C, Barbera TJ, Ritz MC, George FR. Selective serotonin reuptake inhibitors: Effects of chronic treatment on ethanol-reinforced behavior in mice. Alcohol. 1995;**12**(3):177-181. DOI: 10.1016/0741-8329(94)00079-s

[112] Skelly MJ, Weiner JL. Chronic treatment with prazosin or duloxetine lessens concurrent anxiety-like behavior and alcohol intake: Evidence of disrupted noradrenergic signaling in anxiety-related alcohol use. Brain and Behavior. 2014;**4**(4):468-483. DOI:

[113] Alén F, Orio L, Gorriti MA, de Heras RG, Ramírez-López MT, Pozo MA, et al. Increased alcohol consumption in rats after subchronic antidepressant treatment. The International Journal of Neuropsychopharmacology. 2013;**16**:1809-1818. DOI: 10.1017/

[114] Alén F, Serrano A, Gorriti MÁ, Pavón FJ, Orio L, de Heras RG, et al. The administration of atomoxetine during alcohol deprivation induces a timelimited increase in alcohol consumption

after relapse. The International

Journal of Neuropsychopharmacology. 2014;**17**(11):1905-1910. DOI: 10.1017/

10.1002/brb3.230

s1461145713000217

s146114571400087x

acer.13099

[104] Brookwell L, Hogana C, Healya D, Manginb D. Ninety-three cases of alcohol dependence following SSRI treatment. The International Journal of Risk & Safety in Medicine. 2014;**26**: 99-107. DOI: 10.3233/JRS-140616

[105] Menkes DB, Herxheimer A. Interaction between antidepressants and alcohol: Signal amplification by multiple case reports. The International Journal of Risk & Safety in Medicine. 2014;**26**(3):163-170. DOI: 10.3233/

[106] Gimeno C, Dorado ML, Roncero C, Szerman N, Vega P, Balanzá-Martínez V, et al. Treatment of comorbid alcohol dependence and anxiety disorder: Review of the scientific evidence and recommendations for treatment. Frontiers in Psychiatry. 2017;**8**:173. DOI:

10.3389/fpsyt.2017.00173

[107] Barajaz AM, Kliethermes CL. An assessment of the utilization of the preclinical rodent model literature in clinical trials of putative therapeutics for the treatment of alcohol use disorders. Drug and Alcohol Dependence. 2017;**181**:77-84. DOI: 10.1016/j.drugalcdep.2017.09.022

[108] Simon O'Brien E, Legastelois R, Houchi H, Vilpoux C, Alaux-Cantin S, Pierrefiche O, et al. Fluoxetine, desipramine, and the dual antidepressant milnacipran reduce alcohol self-administration and/or relapse in dependent rats. Neuropsychopharmacology. 2011;**36**: 1518-1530. DOI: 10.1038/npp.2011.37

[109] Bell RL, Hauser SR, Liang T, Sari Y, Maldonado-Devincci A, Rodd ZA. Rat animal models for screening medications to treat alcohol use disorders. Neuropharmacology. 2017;**122**:201-243. DOI: 10.1016/j.

[110] Ho AMC, Qiu Y, Jia YF, Aguiar FS, Hinton DJ, Karpyak VM, et al.

neuropharm.2017.02.004

JRS-140632

**36**

The term resistant points out a clinical phenomenon in which there is a lack of response to one or more therapeutic interventions. Resistance to major depressive disorder treatment causes distress to patients and their relatives, and increases the number of hospital admissions, outpatient consultations, use of psychoactive drugs, and treatment costs. Despite its serious medical and psychosocial medical implications, the definition of treatment resistant depression continues to be ambiguous and controversial. The lack of an agreement on definition, as well as the research on the subject being difficult, limits the practical knowledge on the best treatment options for groups of treatment resistant depression (TRD) patients. We review the concept and definitions of treatment resistant depression as well as the medical literature on different treatment methods studied and comparative studies. Finally, some relevant neurobiological data are reviewed.

**Keywords:** treatment, major depressive disorder, resistant depression, antidepressants, review

#### **1. Introduction**

The term "resistant" is widely employed in medical practice to point out a clinical phenomenon in which there is a lack of response to one or more therapeutic interventions. The presence of treatment resistance implies a specific series of clinical interventions, typically multidisciplinary, and focuses on solving or minimizing a medical problem. Resistance to major depressive disorder treatment, but also to other depressive disorders, such as dysthymia and bipolar depression, causes distress to patients and their relatives, and increases the number of hospital admissions, outpatient consultations, the use of psychoactive drugs, and treatment costs up to six times [1]. The definition of treatment resistant depression (TRD) continues to be ambiguous and controversial despite its serious medical and psychosocial implications. In medical literature, we can find more than 10 different definitions [2]. Many authors have published staging systems with their own definitions, descriptions, and characteristics on TRD [3–7]. The most accepted definition is a lack of response to two different pharmacological classes of antidepressants [8]. However, this definition may seem simplistic today as published treatment results on TRD patients emerge. The lack of an agreed TRD definition as well as the difficulties to do research on the subject limit our practical knowledge on the best treatment options for groups of TRD patients.

We review the concept and definitions of TRD. We also review the medical literature on different treatment methods studied as well as comparative studies. Finally, we review some relevant emerging neurobiological data.

#### **2. Treatment resistance depression (TRD)**

#### **2.1 The concept of resistant depression**

Although this phenomenon had already been described, many authors have introduced the concept of TRD since 1974 [9, 10]. This concept arises at a time when there were only tricyclic, tetracyclic, and monoamine-oxidase inhibitors (MAOIs) antidepressants available. In spite of its importance, the definition of treatment resistance regarding major depression continues to be a wide and inconsistent notion. A review of the literature identifies a range of definitions for TRD that go from non-response to a single antidepressant (for 4 or more weeks) to lack of response to different classes of antidepressants and electroconvulsive therapy (ECT) [2]. Treatment should be appropriate in dose and duration [2, 11–13], and patients must have full compliance to it [13] to consider a patient as resistant to treatment. There is no consensus on the number of treatments and when these are indicators of resistance.

A dichotomic denomination has been proposed for resistant depression, viz. an absolute and a relative. Absolute resistance is an inappropriate anti-depressive response toward a treatment given for an appropriate period of time at the maximum non-toxic dose. On the other hand, relative resistance to treatment is defined when this is given at a suboptimal dose or duration [5, 10, 14]. The terms "chronic," "refractory," and "difficult-to-treat depression" have been employed as synonyms in the absence of a nonspecific number of clinical trials for one or more antidepressants. Treatment refractory depression refers to major depression that does not respond to multiple sequential treatments. There is no clear difference between treatment resistant depression and refractory depression [5, 8, 11]. Chronicity, however, refers to a pathological clinical phenomenon that lasts for 2 or more years. There is no consensus on depressive symptom severity to consider it as resistant. It has been suggested that a score of 16 or more on the Hamilton depression 17-item scale (HAM-D) is enough to confirm the diagnosis. However, patients with persistent mild or moderate depressive symptoms may have a worse prognosis than those in remission [15]. The definition of Berlim and Turecki [2], which considers TRD as an episode of major depression that has not improved after two proper attempts with different classes of antidepressants, prevails today. The European Medicine Agency (EMA), on a TRD definition review, considers it as a clinically relevant major depression that has not benefited from at least two appropriate attempts of treatment with at least two antidepressants with a different action mechanism [16]. The definition which considers TRD as an episode of major depression that has not improved after two proper attempts with different classes of antidepressants [2] seems to be backed up by the STAR\*D study, which shows that improvement chances diminish after the second treatment failure [17, 18]. Treatment resistance to pharmacologic treatment seems to move on a continuum that ranges from total response to total resistance to therapeutic intervention and not as an all-or-nothing phenomenon [5, 19, 20]. However, no definition has been investigated regarding validity and predictability [5, 21]. Inconsistencies on the definition not only give rise to difficulties at estimating its prevalence [17, 22] but can also delay research of the most efficient treatment schemes.

#### **2.2 Prevalence of resistant depression**

In spite of pharmacological treatment advances in major depression, the final objective of achieving a sustained improvement continues to be insufficient [23]. It is estimated that about only 30–40% of patients achieve remission after the first attempt of treatment with antidepressants. In 3671 ambulatory patients treated

**39**

*Resistant Depression*

**systems**

*DOI: http://dx.doi.org/10.5772/intechopen.82568*

ated to longer time of treatment and increased costs [29].

*2.3.1 Antidepressant treatment assessment scales*

determine treatment response or resistance [31].

*2.3.2 Treatment resistant depression stratification systems*

ness, they have not been properly validated.

remote interviews [36].

latter is performed by the patient.

with escitalopram, only 37% achieved remission [18]. Even after an appropriate sequence of treatments, 10–20% of the patients with major depression continue with significant symptoms for 2 years or more [24, 25]. The STAR\*D study (sequenced treatment alternatives to relieve depression study) showed that accumulated remission after four treatment trials with antidepressants for 14 months was 67% [26]. Patients with chronic depression seem to have less opportunity for recovery [27] and tend to be more resistant to treatment [1, 28]. TRD is also associ-

**2.3 Antidepressant treatment resistance assessment scales and stratification** 

From the multiple published assessment scales, three of them stand out in literature: the Antidepressant Treatment History Form [30], the Harvard Antidepressant Treatment History [31], and the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire [6]. The clinician performs the former two; the

The Antidepressant Treatment History Form (ATHF; 1990; revised 1999) was originally designed to assess the efficacy of antidepressant treatment before ECT [30]. The scale has five treatment levels, which go from 0 (no treatment) to 5 (high antidepressant doses plus lithium or triiodothyronine (T3) for at least 4 weeks, including antipsychotics in patients with depression and psychotic symptoms. The scale has been modified and recently digitalized [32]. This scale has the disadvantage of not including pharmacological combination strategies or preferences on switching treatment [33]. The Antidepressant Treatment History Form has been empirically validated with the monitoring of prospective treatment [8, 33–35]. The original ATHF version has a good inter-rater reliability [3], and the digitalized version has an excellent inter-rater reliability as well, with another evaluator [32]. The Harvard Antidepressant Treatment History (HATH) allows to systematically assess the dose and duration of previous antidepressant medication trials. The patient identifies all the antidepressants taken from a list of all available once, a series of systematic questions over dose, duration, and response are asked to

The Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (ATRQ ) is an auto-evaluating scale that defines an appropriate antidepressant treatment as optimal dosage during 6 weeks. This questionnaire provides operational criteria for adequate dosing of each antidepressant and has been used on multiple multicentric studies in TRD. In one study, it was found that MGH and ATRQ agree with the independent evaluations of clinical researchers on

Systems may help predict the ulterior course of depression on the long-term and its response to treatment [1]. It is important to point out that all systems based on treatment administration have limitations; they were designed when therapeutic options available at the time were more limited, and despite their clinical useful-

Four stratification systems stand out in literature: the Staging Method of Thase and Rush [4], the European Staging Method [5, 37], the Massachusetts General Hospital Staging model (MGH-s) [6], and The Maudsley Staging Model (MSM) [7].

#### *Resistant Depression DOI: http://dx.doi.org/10.5772/intechopen.82568*

*Antidepressants - Preclinical, Clinical and Translational Aspects*

number of treatments and when these are indicators of resistance.

Although this phenomenon had already been described, many authors have introduced the concept of TRD since 1974 [9, 10]. This concept arises at a time when there were only tricyclic, tetracyclic, and monoamine-oxidase inhibitors (MAOIs) antidepressants available. In spite of its importance, the definition of treatment resistance regarding major depression continues to be a wide and inconsistent notion. A review of the literature identifies a range of definitions for TRD that go from non-response to a single antidepressant (for 4 or more weeks) to lack of response to different classes of antidepressants and electroconvulsive therapy (ECT) [2]. Treatment should be appropriate in dose and duration [2, 11–13], and patients must have full compliance to it [13] to consider a patient as resistant to treatment. There is no consensus on the

A dichotomic denomination has been proposed for resistant depression, viz. an absolute and a relative. Absolute resistance is an inappropriate anti-depressive response toward a treatment given for an appropriate period of time at the maximum non-toxic dose. On the other hand, relative resistance to treatment is defined when this is given at a suboptimal dose or duration [5, 10, 14]. The terms "chronic," "refractory," and "difficult-to-treat depression" have been employed as synonyms in the absence of a nonspecific number of clinical trials for one or more antidepressants. Treatment refractory depression refers to major depression that does not respond to multiple sequential treatments. There is no clear difference between treatment resistant depression and refractory depression [5, 8, 11]. Chronicity, however, refers to a pathological clinical phenomenon that lasts for 2 or more years. There is no consensus on depressive symptom severity to consider it as resistant. It has been suggested that a score of 16 or more on the Hamilton depression 17-item scale (HAM-D) is enough to confirm the diagnosis. However, patients with persistent mild or moderate depressive symptoms may have a worse prognosis than those in remission [15]. The definition of Berlim and Turecki [2], which considers TRD as an episode of major depression that has not improved after two proper attempts with different classes of antidepressants, prevails today. The European Medicine Agency (EMA), on a TRD definition review, considers it as a clinically relevant major depression that has not benefited from at least two appropriate attempts of treatment with at least two antidepressants with a different action mechanism [16]. The definition which considers TRD as an episode of major depression that has not improved after two proper attempts with different classes of antidepressants [2] seems to be backed up by the STAR\*D study, which shows that improvement chances diminish after the second treatment failure [17, 18]. Treatment resistance to pharmacologic treatment seems to move on a continuum that ranges from total response to total resistance to therapeutic intervention and not as an all-or-nothing phenomenon [5, 19, 20]. However, no definition has been investigated regarding validity and predictability [5, 21]. Inconsistencies on the definition not only give rise to difficulties at estimating its prevalence [17, 22] but can also delay research of

In spite of pharmacological treatment advances in major depression, the final objective of achieving a sustained improvement continues to be insufficient [23]. It is estimated that about only 30–40% of patients achieve remission after the first attempt of treatment with antidepressants. In 3671 ambulatory patients treated

**2. Treatment resistance depression (TRD)**

**2.1 The concept of resistant depression**

**38**

the most efficient treatment schemes.

**2.2 Prevalence of resistant depression**

with escitalopram, only 37% achieved remission [18]. Even after an appropriate sequence of treatments, 10–20% of the patients with major depression continue with significant symptoms for 2 years or more [24, 25]. The STAR\*D study (sequenced treatment alternatives to relieve depression study) showed that accumulated remission after four treatment trials with antidepressants for 14 months was 67% [26]. Patients with chronic depression seem to have less opportunity for recovery [27] and tend to be more resistant to treatment [1, 28]. TRD is also associated to longer time of treatment and increased costs [29].

#### **2.3 Antidepressant treatment resistance assessment scales and stratification systems**

#### *2.3.1 Antidepressant treatment assessment scales*

From the multiple published assessment scales, three of them stand out in literature: the Antidepressant Treatment History Form [30], the Harvard Antidepressant Treatment History [31], and the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire [6]. The clinician performs the former two; the latter is performed by the patient.

The Antidepressant Treatment History Form (ATHF; 1990; revised 1999) was originally designed to assess the efficacy of antidepressant treatment before ECT [30]. The scale has five treatment levels, which go from 0 (no treatment) to 5 (high antidepressant doses plus lithium or triiodothyronine (T3) for at least 4 weeks, including antipsychotics in patients with depression and psychotic symptoms. The scale has been modified and recently digitalized [32]. This scale has the disadvantage of not including pharmacological combination strategies or preferences on switching treatment [33]. The Antidepressant Treatment History Form has been empirically validated with the monitoring of prospective treatment [8, 33–35]. The original ATHF version has a good inter-rater reliability [3], and the digitalized version has an excellent inter-rater reliability as well, with another evaluator [32].

The Harvard Antidepressant Treatment History (HATH) allows to systematically assess the dose and duration of previous antidepressant medication trials. The patient identifies all the antidepressants taken from a list of all available once, a series of systematic questions over dose, duration, and response are asked to determine treatment response or resistance [31].

The Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (ATRQ ) is an auto-evaluating scale that defines an appropriate antidepressant treatment as optimal dosage during 6 weeks. This questionnaire provides operational criteria for adequate dosing of each antidepressant and has been used on multiple multicentric studies in TRD. In one study, it was found that MGH and ATRQ agree with the independent evaluations of clinical researchers on remote interviews [36].

#### *2.3.2 Treatment resistant depression stratification systems*

Systems may help predict the ulterior course of depression on the long-term and its response to treatment [1]. It is important to point out that all systems based on treatment administration have limitations; they were designed when therapeutic options available at the time were more limited, and despite their clinical usefulness, they have not been properly validated.

Four stratification systems stand out in literature: the Staging Method of Thase and Rush [4], the European Staging Method [5, 37], the Massachusetts General Hospital Staging model (MGH-s) [6], and The Maudsley Staging Model (MSM) [7].

Thase and Rush proposed five levels of resistance, in which patients are categorized according to the number and antidepressant class they have failed to respond, from the most frequently used to the least usual as MAOIs or ECT [4]. Not one degree of each therapeutic trial in terms of dose and duration is recorded; it assumes that the non-response to two antidepressant agents of different classes is more difficult to treat than the non-response to agents of the same group and that the change to an antidepressant of the same group is less effective. The later may be true for tricyclic antidepressants, but it is not so at switching between different serotonin reuptake inhibitors (SSRIs) [17]. This classification considers that the most effective antidepressants on order would be MAOIs, tricyclic antidepressants, and SSRIs, which has not been validated on different meta-analyses in antidepressant trials [17, 20]. It also faces the disadvantage of not including other treatments, such as drug combinations and psychotherapy, and does not provide prognostic information [38]. The Thase and Rush scale is easy to implement and provides an accessible strategy for clinicians to treat TRD patients. However, it has been widely criticized recently, since its predictive value over the course of treatment has not been systematically evaluated [8, 33, 34].

A European Staging Method (ESM) proposes the classification between non-responders, patients with TRD, and chronic resistant depression (CRD). Non-responders are defined as patients who fail to respond to a method of treatment. Patients are considered TRD if they show poor response to two treatment options with different classes of antidepressants at a proper dose over the span of 6–8 weeks. CRD is defined as a resistant or refractory episode that lasts for more than a year despite appropriate therapeutic interventions. This scale has the advantage of including the duration of the depressive episodes and does not suggest a hierarchy of antidepressants. Non-response is clearly defined as a reduction inferior to 50% on the score of the HAMD [39] or the Montgomery Asberg Depression Rating Scale (MADRS) [40] and the TRD stages correspond to the number of failed therapeutic trials. It is assumed that patients with failure to respond to two agents of different classes would be more resistant than those who do not respond to two drugs of the same group and indirectly implies that switching to a drug from the same class is less effective [6]. It should be noted that, in this classification, the differences between TRD and CRD are arbitrary [8]. ESM does not establish that two or more attempts with failed antidepressants imply a higher level of TRD, in contrast with the publications that associate the number of changes with poor response to treatment [17, 18]. Furthermore, CRD does not consider non-pharmacological measures such as ECT or psychotherapy. To date, there are no studies that prove the predictive utility or reliability of the scale.

The Massachusetts General Hospital Staging model (MGH-s) was published for the first time by Fava [6] based on the scale by Thase and Rush. The MGH-s considers dosage optimization and separately prolonging the duration of treatment, as well as an operational criterion for minimal dose and duration of treatment. It includes measures for titration and combinations and does not rank antidepressant classes [41] or an implied preference between them or a change to the same group of drugs. The MGH-s considers the number of failed treatments and the intensity and optimization of each attempt and generates a continuous variable that reflects the degree of resistance to antidepressants. MGH-s generates a continuous score that reflects the level of resistance. However, this score is randomly given [8]. Dosage optimization and duration are considered equal to increase or combination, which does not seem to be backed up on literature [42–44]. Finally, the higher score given to ECT is not sufficiently explained [7, 45].

A study published a comparison between the MGH-s and the Thase and Rush Staging Method on a sample of 115 ambulatory patients with major depression. All

**41**

*Resistant Depression*

*DOI: http://dx.doi.org/10.5772/intechopen.82568*

**2.4 Resistant depression treatment general principles**

ideation, psychotic or catatonic behavior are detected.

*2.4.1 Treatment strategies*

*2.4.1.1 Optimization*

results showed that both models have a high correlation, but the multivariable analysis demonstrated that the MGH-s had a better prediction for non-remission [45]. Fedaku et al. [7] published The Maudsley Staging Model (MSM) method of stratification, in which the TDR score varies from 3 to 15. TRD stages are shown in three categories: mild (scores 3–6), moderate (scores 7–10), and severe (scores 11–15). It incorporates the duration and severity of the depressive episode. MSM considers class switching between different antidepressant groups, and between the same group has the same score. The scale is easy to use and may be employed as a tridimensional model regarding duration, severity, and treatment. It has been criticized, however, that disease duration is arbitrary and does not include the number of titrating attempts. Empiric value and inter-rate reliability was proven with prospective data obtained from the notes of 88 patients on a TRD specialized unit and follow-up of 62 patients in this group for a medium of 29.5 months [7].

Qualitative and quantitative assessment of depressive symptoms with evaluation scales on each visit, assessment tool employment, and watching over adverse effects should be a routine practice in the approach to the patient with major depressive disorder, and even more so with the TRD patient. Furthermore, it is recommended to evaluate psychosocial performance, quality of life, treatment compliance and tolerance, and provide 24-h assistance [46]. It is important to encourage patients not to abandon treatment or medical attention despite of not perceiving any results. A good relationship between the clinician and the patient is also important to guarantee treatment compliance [15]. Finally, the role of psycho-education for the patients and their relatives should not be forgotten, as this includes sign and symptom identification, prognosis, suicide risk assessment, treatment options, sleep hygiene, impulse control, and sleep restriction among others. Behind restriction the initial management of depressive patients is usually done by primary care physicians or internists, but they should be referred to a mental health specialist if there is not an appropriate response to two or more treatments, as well when suicidal or homicidal

For patients with major depressive disorder who do not respond to initial treatment with an antidepressant, there are diverse management strategies [5, 14, 30, 47–50] which have been classified and arranged in three groups as follows: (1) optimization; (2) treatment switching (to a different antidepressant, psychotherapy, or ECT); (3) augmentation or adding other treatment to the one already in use, such as a different drug, psychotherapy, or ECT (**Table 1**). Regardless of the strategy, it is recommended always to use one strategy at a time

Optimization consists of improving the current treatment, while supervising good tolerance. It should be noted that, in some studies with patients diagnosed as resistant and sent to specialized clinics, it has been reported that an important number of them did not receive an appropriate dose of the medication or had been taking it behind for a brief period of time [51]. This would represent a case of pseudo-resistance. Several studies show that it is important to treat a major depressive episode for 6–12 weeks before concluding non-remittance [6, 26, 52]. A study in

to assess which is the most effective. We will review each one of them.

#### *Resistant Depression DOI: http://dx.doi.org/10.5772/intechopen.82568*

*Antidepressants - Preclinical, Clinical and Translational Aspects*

been systematically evaluated [8, 33, 34].

predictive utility or reliability of the scale.

to ECT is not sufficiently explained [7, 45].

Thase and Rush proposed five levels of resistance, in which patients are categorized according to the number and antidepressant class they have failed to respond, from the most frequently used to the least usual as MAOIs or ECT [4]. Not one degree of each therapeutic trial in terms of dose and duration is recorded; it assumes that the non-response to two antidepressant agents of different classes is more difficult to treat than the non-response to agents of the same group and that the change to an antidepressant of the same group is less effective. The later may be true for tricyclic antidepressants, but it is not so at switching between different serotonin reuptake inhibitors (SSRIs) [17]. This classification considers that the most effective antidepressants on order would be MAOIs, tricyclic antidepressants, and SSRIs, which has not been validated on different meta-analyses in antidepressant trials [17, 20]. It also faces the disadvantage of not including other treatments, such as drug combinations and psychotherapy, and does not provide prognostic information [38]. The Thase and Rush scale is easy to implement and provides an accessible strategy for clinicians to treat TRD patients. However, it has been widely criticized recently, since its predictive value over the course of treatment has not

A European Staging Method (ESM) proposes the classification between non-responders, patients with TRD, and chronic resistant depression (CRD). Non-responders are defined as patients who fail to respond to a method of treatment. Patients are considered TRD if they show poor response to two treatment options with different classes of antidepressants at a proper dose over the span of 6–8 weeks. CRD is defined as a resistant or refractory episode that lasts for more than a year despite appropriate therapeutic interventions. This scale has the advantage of including the duration of the depressive episodes and does not suggest a hierarchy of antidepressants. Non-response is clearly defined as a reduction inferior to 50% on the score of the HAMD [39] or the Montgomery Asberg Depression Rating Scale (MADRS) [40] and the TRD stages correspond to the number of failed therapeutic trials. It is assumed that patients with failure to respond to two agents of different classes would be more resistant than those who do not respond to two drugs of the same group and indirectly implies that switching to a drug from the same class is less effective [6]. It should be noted that, in this classification, the differences between TRD and CRD are arbitrary [8]. ESM does not establish that two or more attempts with failed antidepressants imply a higher level of TRD, in contrast with the publications that associate the number of changes with poor response to treatment [17, 18]. Furthermore, CRD does not consider non-pharmacological measures such as ECT or psychotherapy. To date, there are no studies that prove the

The Massachusetts General Hospital Staging model (MGH-s) was published for the first time by Fava [6] based on the scale by Thase and Rush. The MGH-s considers dosage optimization and separately prolonging the duration of treatment, as well as an operational criterion for minimal dose and duration of treatment. It includes measures for titration and combinations and does not rank antidepressant classes [41] or an implied preference between them or a change to the same group of drugs. The MGH-s considers the number of failed treatments and the intensity and optimization of each attempt and generates a continuous variable that reflects the degree of resistance to antidepressants. MGH-s generates a continuous score that reflects the level of resistance. However, this score is randomly given [8]. Dosage optimization and duration are considered equal to increase or combination, which does not seem to be backed up on literature [42–44]. Finally, the higher score given

A study published a comparison between the MGH-s and the Thase and Rush Staging Method on a sample of 115 ambulatory patients with major depression. All

**40**

results showed that both models have a high correlation, but the multivariable analysis demonstrated that the MGH-s had a better prediction for non-remission [45].

Fedaku et al. [7] published The Maudsley Staging Model (MSM) method of stratification, in which the TDR score varies from 3 to 15. TRD stages are shown in three categories: mild (scores 3–6), moderate (scores 7–10), and severe (scores 11–15). It incorporates the duration and severity of the depressive episode. MSM considers class switching between different antidepressant groups, and between the same group has the same score. The scale is easy to use and may be employed as a tridimensional model regarding duration, severity, and treatment. It has been criticized, however, that disease duration is arbitrary and does not include the number of titrating attempts. Empiric value and inter-rate reliability was proven with prospective data obtained from the notes of 88 patients on a TRD specialized unit and follow-up of 62 patients in this group for a medium of 29.5 months [7].

#### **2.4 Resistant depression treatment general principles**

Qualitative and quantitative assessment of depressive symptoms with evaluation scales on each visit, assessment tool employment, and watching over adverse effects should be a routine practice in the approach to the patient with major depressive disorder, and even more so with the TRD patient. Furthermore, it is recommended to evaluate psychosocial performance, quality of life, treatment compliance and tolerance, and provide 24-h assistance [46]. It is important to encourage patients not to abandon treatment or medical attention despite of not perceiving any results. A good relationship between the clinician and the patient is also important to guarantee treatment compliance [15]. Finally, the role of psycho-education for the patients and their relatives should not be forgotten, as this includes sign and symptom identification, prognosis, suicide risk assessment, treatment options, sleep hygiene, impulse control, and sleep restriction among others. Behind restriction the initial management of depressive patients is usually done by primary care physicians or internists, but they should be referred to a mental health specialist if there is not an appropriate response to two or more treatments, as well when suicidal or homicidal ideation, psychotic or catatonic behavior are detected.

#### *2.4.1 Treatment strategies*

For patients with major depressive disorder who do not respond to initial treatment with an antidepressant, there are diverse management strategies [5, 14, 30, 47–50] which have been classified and arranged in three groups as follows: (1) optimization; (2) treatment switching (to a different antidepressant, psychotherapy, or ECT); (3) augmentation or adding other treatment to the one already in use, such as a different drug, psychotherapy, or ECT (**Table 1**). Regardless of the strategy, it is recommended always to use one strategy at a time to assess which is the most effective. We will review each one of them.

#### *2.4.1.1 Optimization*

Optimization consists of improving the current treatment, while supervising good tolerance. It should be noted that, in some studies with patients diagnosed as resistant and sent to specialized clinics, it has been reported that an important number of them did not receive an appropriate dose of the medication or had been taking it behind for a brief period of time [51]. This would represent a case of pseudo-resistance. Several studies show that it is important to treat a major depressive episode for 6–12 weeks before concluding non-remittance [6, 26, 52]. A study in


#### **Table 1.**

*Treatment strategies for resistant depression.*

1627 patients, where 67% of them received less than 4 weeks of treatment and did not show response to an antidepressant [53], did not find any difference between continuing the current treatment or changing to another antidepressant. This supports the importance of keeping the patients on an antidepressant treatment for an appropriate amount of time before changing it. On the other hand, multiple studies show that if patients have less than 25% reduction of symptoms after 4 weeks treatment, it could be indicated to switch to a different treatment strategy [54].

#### *2.4.1.2 Treatment switching*

Treatment switching is the act of suspending the current treatment and replacing it with a different pharmacologic or non-pharmacologic anti-depressive strategy. This includes using a different antidepressant, switching to psychotherapy, or ECT.

#### *2.4.1.3 Changing antidepressants*

It has been suggested that, in order to switch antidepressant medications, the current medication should be gradually discontinued while the new one is slowly introduced throughout 1–2 weeks and the dosage of the new antidepressant agent should be given at a corresponding amount to the one being discontinued. The clinician should be aware of increases of adverse effects and, in relation to SSRIs, the risk of serotonin syndrome. Some clinicians prefer to switch from an SSRI to another instantly, except when the patient has received fluoxetine, where the waiting time should be no less than 4 weeks before using another SSRI due to its long half-life.

For patients resistant to SSRIs, it has been suggested to switch to a selective noradrenaline and serotonin reuptake inhibitor (SNRI), atypical antidepressants, such as bupropion or mirtazapine, tricyclic antidepressants, or MAOIs. There are, however, few studies that compare switching to each one of these groups of drugs. In one meta-analysis that included four randomized studies with 1496 patients resistant to an SSRI, remission was evident in 24% of the patients who received another SSRI, and in 28% who were introduced to a different class of antidepressant such as bupropion, mirtazapine, or venlafaxine [55]. Regarding patients resistant to SSRI, many studies, including some meta-analyses, support changing to venlafaxine [17, 55]. A metaanalysis with 3375 patients with depression resistant to an SSRI showed that changing to another SSRI led to remission on 45% of the subjects, but 54% remitted when changing to venlafaxine [17]. Concerning atypical antidepressants, the few comparative studies available on TRD patients have not found differences respecting efficacy [18, 42]. In a group of patients resistant to paroxetine, a study that compared extended

**43**

*2.4.1.4 Switching to psychotherapy*

*2.4.1.5 Electroconvulsive therapy*

*Resistant Depression*

*DOI: http://dx.doi.org/10.5772/intechopen.82568*

release venlafaxine (225 mg/day) and mirtazapine (45 mg/day) found remissions of 41 and 36% respectively [56]. In another study, 477 patients resistant to an SSRI treated for 14 weeks with bupropion SR (average dose 238 mg/day) or sertraline (average dose 136 mg/day) remission was achieved on 21 and 18% of the subjects, respectively [57]. An 8-week study that compared mirtazapine (45 mg/day) with paroxetine (20 mg/ day) in 100 patients with TRD, remission was achieved in 36 and 47% with similar tolerance. Finally, a comparative study with mirtazapine (average dose 30 mg/day) and sertraline (average dose 120 mg/day) in 250 TRD patients, remission was similar (38 versus 28%, respectively) without statistical difference [58–60]. Nevertheless, there were more adverse effects with mirtazapine such as sedation, fatigue, weight gain, and xerostomia. In TRD patients, efficacy and tolerability of tricyclic antidepressants is comparable to that of atypical antidepressants and SSRIs [61]. Currently, tricyclic antidepressants have become the fourth or fifth line of treatment in TRD patients due to undesired adverse effects such as anticholinergic effects, cardiotoxicity, and lethal potential with overdose. The STAR\*D study reported the fourth or fifth line of treatment in major depressive patients due to undesired adverse effects such as anticholinergic effects, cardiotoxicity, and lethal potential with overdose. In TRD patients, efficacy and tolerability of tricyclic antidepressants is comparable to that of atypical antidepressants and SSRIs. In the STAR\*D study, an open 14-week trial in 235 patients compared nortriptyline (average dose 97 mg/day) with mirtazapine (average dose 42 mg/day) showing a comparable remission of 20 versus 12% and equal tolerance [62]. In a double-blind randomized study, 168 imipramine- or sertraline-resistant patients treated for 12 weeks were randomly assigned to the other treatment [63]. Remission was comparable (23% versus 32%) with more discontinuation with imipramine switching due to adverse effects (9 versus 0%). MAOIs are rarely used today, since they carry lethal potential by interacting with other drugs and food containing tyramine [64]. Nevertheless, changing to a MAOI may still be helpful for some TRD patients [17, 64]. A randomized trial with 46 imipramine-resistant patients who received phenelzine (45–90 mg/day) for 6 weeks and 22 phenelzine-resistant patients who were switched to imipramine (150–300 mg/day) reported a higher response on patients who received phenelzine rather than imipramine (67 versus 41%) [64]. For severely depressed patients with TRD, there is not enough evidence that indicates which kind of antidepressant is superior [65]. Tricyclic antidepressants may be preferred [66]. However, a meta-analysis of 25 randomized trials on 1377 hospitalized depressed patients who received tricyclic antidepressants or SSRIs showed that tricyclic antidepressant superiority over SSRIs was low with a higher rate of adverse effects [67].

Changing from a pharmacologic approach to psychotherapy may be rejected by many TRD patients [68], but still is a reasonable approach. A 12-week trial with 122 patients who did not respond to citalopram and were randomized to cognitive behavioral therapy (CBT) or different antidepressants (bupropion, sertraline, or venlafaxine) [68] reported similar remission (25 and 28%). Another study with 140 patients who did not respond to a trial with nefazodone or CBT and then were switched to the other treatment [69] reported a comparable remission of 36 and 27%, respectively.

For patients with TRD with severe depression, ECT continues to be the therapy of choice [28, 66, 70–72]. The most important indications for ECT are persistence of suicidal ideation, suicide attempt, severe weight loss with malnutrition, dehydration, food or fluids rejection, and malignant catatonia. ECT is also indicated in cases

#### *Resistant Depression DOI: http://dx.doi.org/10.5772/intechopen.82568*

*Antidepressants - Preclinical, Clinical and Translational Aspects*

1627 patients, where 67% of them received less than 4 weeks of treatment and did not show response to an antidepressant [53], did not find any difference between continuing the current treatment or changing to another antidepressant. This supports the importance of keeping the patients on an antidepressant treatment for an appropriate amount of time before changing it. On the other hand, multiple studies show that if patients have less than 25% reduction of symptoms after 4 weeks treat-

Treatment switching is the act of suspending the current treatment and replacing it with a different pharmacologic or non-pharmacologic anti-depressive strategy. This includes using a different antidepressant, switching to psychotherapy, or ECT.

It has been suggested that, in order to switch antidepressant medications, the current medication should be gradually discontinued while the new one is slowly introduced throughout 1–2 weeks and the dosage of the new antidepressant agent should be given at a corresponding amount to the one being discontinued. The clinician should be aware of increases of adverse effects and, in relation to SSRIs, the risk of serotonin syndrome. Some clinicians prefer to switch from an SSRI to another instantly, except when the patient has received fluoxetine, where the waiting time should be no less than 4 weeks before using another SSRI due to its long half-life. For patients resistant to SSRIs, it has been suggested to switch to a selective noradrenaline and serotonin reuptake inhibitor (SNRI), atypical antidepressants, such as bupropion or mirtazapine, tricyclic antidepressants, or MAOIs. There are, however, few studies that compare switching to each one of these groups of drugs. In one meta-analysis that included four randomized studies with 1496 patients resistant to an SSRI, remission was evident in 24% of the patients who received another SSRI, and in 28% who were introduced to a different class of antidepressant such as bupropion, mirtazapine, or venlafaxine [55]. Regarding patients resistant to SSRI, many studies, including some meta-analyses, support changing to venlafaxine [17, 55]. A metaanalysis with 3375 patients with depression resistant to an SSRI showed that changing to another SSRI led to remission on 45% of the subjects, but 54% remitted when changing to venlafaxine [17]. Concerning atypical antidepressants, the few comparative studies available on TRD patients have not found differences respecting efficacy [18, 42]. In a group of patients resistant to paroxetine, a study that compared extended

ment, it could be indicated to switch to a different treatment strategy [54].

*2.4.1.2 Treatment switching*

*Treatment strategies for resistant depression.*

**Table 1.**

*2.4.1.3 Changing antidepressants*

**42**

release venlafaxine (225 mg/day) and mirtazapine (45 mg/day) found remissions of 41 and 36% respectively [56]. In another study, 477 patients resistant to an SSRI treated for 14 weeks with bupropion SR (average dose 238 mg/day) or sertraline (average dose 136 mg/day) remission was achieved on 21 and 18% of the subjects, respectively [57]. An 8-week study that compared mirtazapine (45 mg/day) with paroxetine (20 mg/ day) in 100 patients with TRD, remission was achieved in 36 and 47% with similar tolerance. Finally, a comparative study with mirtazapine (average dose 30 mg/day) and sertraline (average dose 120 mg/day) in 250 TRD patients, remission was similar (38 versus 28%, respectively) without statistical difference [58–60]. Nevertheless, there were more adverse effects with mirtazapine such as sedation, fatigue, weight gain, and xerostomia. In TRD patients, efficacy and tolerability of tricyclic antidepressants is comparable to that of atypical antidepressants and SSRIs [61]. Currently, tricyclic antidepressants have become the fourth or fifth line of treatment in TRD patients due to undesired adverse effects such as anticholinergic effects, cardiotoxicity, and lethal potential with overdose. The STAR\*D study reported the fourth or fifth line of treatment in major depressive patients due to undesired adverse effects such as anticholinergic effects, cardiotoxicity, and lethal potential with overdose. In TRD patients, efficacy and tolerability of tricyclic antidepressants is comparable to that of atypical antidepressants and SSRIs. In the STAR\*D study, an open 14-week trial in 235 patients compared nortriptyline (average dose 97 mg/day) with mirtazapine (average dose 42 mg/day) showing a comparable remission of 20 versus 12% and equal tolerance [62]. In a double-blind randomized study, 168 imipramine- or sertraline-resistant patients treated for 12 weeks were randomly assigned to the other treatment [63]. Remission was comparable (23% versus 32%) with more discontinuation with imipramine switching due to adverse effects (9 versus 0%). MAOIs are rarely used today, since they carry lethal potential by interacting with other drugs and food containing tyramine [64]. Nevertheless, changing to a MAOI may still be helpful for some TRD patients [17, 64]. A randomized trial with 46 imipramine-resistant patients who received phenelzine (45–90 mg/day) for 6 weeks and 22 phenelzine-resistant patients who were switched to imipramine (150–300 mg/day) reported a higher response on patients who received phenelzine rather than imipramine (67 versus 41%) [64]. For severely depressed patients with TRD, there is not enough evidence that indicates which kind of antidepressant is superior [65]. Tricyclic antidepressants may be preferred [66]. However, a meta-analysis of 25 randomized trials on 1377 hospitalized depressed patients who received tricyclic antidepressants or SSRIs showed that tricyclic antidepressant superiority over SSRIs was low with a higher rate of adverse effects [67].

#### *2.4.1.4 Switching to psychotherapy*

Changing from a pharmacologic approach to psychotherapy may be rejected by many TRD patients [68], but still is a reasonable approach. A 12-week trial with 122 patients who did not respond to citalopram and were randomized to cognitive behavioral therapy (CBT) or different antidepressants (bupropion, sertraline, or venlafaxine) [68] reported similar remission (25 and 28%). Another study with 140 patients who did not respond to a trial with nefazodone or CBT and then were switched to the other treatment [69] reported a comparable remission of 36 and 27%, respectively.

#### *2.4.1.5 Electroconvulsive therapy*

For patients with TRD with severe depression, ECT continues to be the therapy of choice [28, 66, 70–72]. The most important indications for ECT are persistence of suicidal ideation, suicide attempt, severe weight loss with malnutrition, dehydration, food or fluids rejection, and malignant catatonia. ECT is also indicated in cases of depression with psychotic symptoms and if there is previous history of response to this treatment. ECT has been shown superior to pharmacotherapy as shown by multiple meta-analyses and randomized studies [65]. A meta-analysis of 18 studies with 1144 patients that compared ECT with pharmacotherapy found that ECT was more effective [71]. ECT approach is recommended by many guidelines [66, 70, 72, 73]. ECT is not exempt of anesthetic risks, adverse effects, logistic problems, treatment rejection, and relapse.

#### *2.4.1.6 Augmentation*

Augmentation consists of adding other treatment (pharmacologic or nonpharmacologic) to the current one [74]. A new drug, psychotherapy, or transcranial magnetic stimulation (TME) might be added. This approach has been widely used and studied; combination therapy with antipsychotics, lithium, or triiiodothyronine (T3) are generally well tolerated [52, 58, 75–79], while combination therapy of MAOI with other antidepressants may cause serotonin syndrome or hypertensive crisis [80]. Previous response, safety, comorbidities, ease of use, patient's preference, and costs are factors to consider while adding other drugs to the current treatment. TRD patients, who have had additions and do not respond in 6–12 weeks at the desired dose or do not tolerate the combination, should be switched to a second combination [58]. Some authors suggest discontinuation of the supplementary drug and addition of a new one progressively over 1–2 weeks [58].

#### *2.4.1.7 Adding a second antidepressant*

Concerning depression with partial response to monotherapy with antidepressants, a second drug is usually added. However, a meta-analysis of eight studies with 808 patients that did not respond to monotherapy and that compared antidepressant combination with monotherapy, found a similar improvement on both groups [81]. The most studied antidepressants are mirtazapine and bupropion.

Mirtazapine use as an augmentation drug on TRD patients is supported by the results of open and placebo-controlled studies [81, 82]. On the STAR\*D study, mirtazapine was added to patients resistant to venlafaxine and was compared with switching to tranylcypromine (a MAOI). Both approaches had no different effects [83]. However, addition of mirtazapine to resistant patients requires additional studies to establish its efficacy.

Bupropion, a noradrenergic/dopaminergic reuptake inhibitor, was studied in TRD patients [84]. Bupropion has a good tolerability and low side effect profile, including few sexual side effects.

Buspirone, a serotonin (5-HT1A) receptor partial agonist, was studied in randomized, double-blind, placebo-controlled trials combined with an SSRI in patients with TRD [85]. Buspirone, at a dosage of 41 mg/day, was compared on the STAR\*D study with Bupropion SR at 267 mg/day, with similar effectiveness [44]. As with mirtazapine, bupropion addition is a popular practice as an enhancing maneuver, but additional studies are needed to justify its use on TRD patients.

#### *2.4.1.8 Second-generation antipsychotics*

For second-generation antipsychotics in patients with TRD, the following order was suggested based on benefit and a lower rate of adverse effects: aripiprazole, quetiapine, risperidone, and less frequently ziprasidone or olanzapine [58, 77, 86, 87]. Also, the use of brexpiprazole has been suggested if aripiprazole generates akathisia [88, 89]. The analysis of 16 studies comparing the addition of aripiprazole,

**45**

*Resistant Depression*

*2.4.1.9 Lithium*

*2.4.1.10 Thyroid hormone*

popular in the UK nor in the USA [96].

*2.4.1.11 Repetitive transcranial magnetic stimulation*

*DOI: http://dx.doi.org/10.5772/intechopen.82568*

olanzapine, quetiapine, or risperidone with placebo on 3480 patients with non-psychotic depression who failed to at least one attempt with antidepressant monotherapy [90] showed improvement in 31% of the patients who received the additional drug (31%) versus placebo (17%). Discontinue due to adverse effects was higher with antipsychotics (9 versus 2%), 4% for aripiprazole, 12% for quetiapine, and 7% for risperidone [90]. In an open, randomized 12-week trial with 1522 patients who stayed severely depressed after treatment with an antidepressant [75], the subjects received three types of treatments: aripiprazole increase (target dose 5–15 mg/day), bupropion increase (target dose 300–400 mg/day), or switching to bupropion. Response (reduction equal or higher than 50% of depression) was greater with aripiprazole (74%) than increasing bupropion (66%) or switching to bupropion (62%). There were more adverse effects with aripiprazole, such as akathisia, somnolence, weight gain, and laboratory abnormalities, but patients experienced more anxiety with bupropion. A meta-analysis of 11 randomized trials on TRD patients (n > 3000) found that effectiveness of the augmentation of atypical antipsychotics might rise with the increase of the resistance [90]. For example, the augmentation may carry more benefit for patients that do not respond to three

or four failed attempts compared with those who do not respond to one.

Augmentation of treatment with lithium was reported for the first time by De Montigny by combining it with tricyclic antidepressants [91]. Thereafter, multiple studies have demonstrated its efficacy. A meta-analysis of 10 placebo, controlled studies showed that the addition of lithium at a dose to 600–900 mg/day (plasma levels higher than 0.4 mEq/L) was superior to placebo [78, 92]. A meta-analysis of nine trials with 237 patients comparing lithium versus placebo found a higher response with lithium [84]. Lithium was effective in the augmentation with first- and secondgeneration antidepressants attached to a possible benefit in reducing suicide risk. A meta-analysis of nine studies with 234 patients, where double-blind trials with lithium and placebo on TRD patients were included, showed a broad effectiveness with this approach [93]. The authors concluded that it should be given for no less than 7 days at dose of 600–800 mg/day [93]. An analysis of the literature reviewing 12 randomized studies on lithium augmentation of SSRIs or atypical antipsychotic drug therapy found no statistical difference that favors the use of one approach or the other [94].

Thyroid hormone, in particular T3, has been used as an augmenting agent since the 1960s [95]. The usual dose of T3 in the form of liothyronine is 25–50 pg and with thyroxine (T4) is 150 pg. An initial meta-analysis with T3 showed effectiveness against placebo [79]. Subsequent studies, however, have shown limited evidence of its effectiveness. A meta-analysis with four randomized studies with 95 patients who did not respond to tricyclic antidepressants compared augmentation with T3 versus placebo or T4 showed response in 53% patients who received T3 but had not statistical difference with placebo [79]. However, T3 augmentation is not very

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive technique in which a sequence of high-intensity magnetic pulses is used to stimulate cortical neurons to treat neuropsychiatric disorders including major depressive disorder

#### *Resistant Depression DOI: http://dx.doi.org/10.5772/intechopen.82568*

olanzapine, quetiapine, or risperidone with placebo on 3480 patients with non-psychotic depression who failed to at least one attempt with antidepressant monotherapy [90] showed improvement in 31% of the patients who received the additional drug (31%) versus placebo (17%). Discontinue due to adverse effects was higher with antipsychotics (9 versus 2%), 4% for aripiprazole, 12% for quetiapine, and 7% for risperidone [90]. In an open, randomized 12-week trial with 1522 patients who stayed severely depressed after treatment with an antidepressant [75], the subjects received three types of treatments: aripiprazole increase (target dose 5–15 mg/day), bupropion increase (target dose 300–400 mg/day), or switching to bupropion. Response (reduction equal or higher than 50% of depression) was greater with aripiprazole (74%) than increasing bupropion (66%) or switching to bupropion (62%). There were more adverse effects with aripiprazole, such as akathisia, somnolence, weight gain, and laboratory abnormalities, but patients experienced more anxiety with bupropion. A meta-analysis of 11 randomized trials on TRD patients (n > 3000) found that effectiveness of the augmentation of atypical antipsychotics might rise with the increase of the resistance [90]. For example, the augmentation may carry more benefit for patients that do not respond to three or four failed attempts compared with those who do not respond to one.

#### *2.4.1.9 Lithium*

*Antidepressants - Preclinical, Clinical and Translational Aspects*

treatment rejection, and relapse.

*2.4.1.7 Adding a second antidepressant*

studies to establish its efficacy.

including few sexual side effects.

*2.4.1.8 Second-generation antipsychotics*

*2.4.1.6 Augmentation*

of depression with psychotic symptoms and if there is previous history of response to this treatment. ECT has been shown superior to pharmacotherapy as shown by multiple meta-analyses and randomized studies [65]. A meta-analysis of 18 studies with 1144 patients that compared ECT with pharmacotherapy found that ECT was more effective [71]. ECT approach is recommended by many guidelines [66, 70, 72, 73]. ECT is not exempt of anesthetic risks, adverse effects, logistic problems,

Augmentation consists of adding other treatment (pharmacologic or nonpharmacologic) to the current one [74]. A new drug, psychotherapy, or transcranial magnetic stimulation (TME) might be added. This approach has been widely used and studied; combination therapy with antipsychotics, lithium, or triiiodothyronine (T3) are generally well tolerated [52, 58, 75–79], while combination therapy of MAOI with other antidepressants may cause serotonin syndrome or hypertensive crisis [80]. Previous response, safety, comorbidities, ease of use, patient's preference, and costs are factors to consider while adding other drugs to the current treatment. TRD patients, who have had additions and do not respond in 6–12 weeks at the desired dose or do not tolerate the combination, should be switched to a second combination [58]. Some authors suggest discontinuation of the supplementary drug

Concerning depression with partial response to monotherapy with antidepressants, a second drug is usually added. However, a meta-analysis of eight studies with 808 patients that did not respond to monotherapy and that compared antidepressant combination with monotherapy, found a similar improvement on both groups [81]. The most studied antidepressants are mirtazapine and bupropion. Mirtazapine use as an augmentation drug on TRD patients is supported by the results of open and placebo-controlled studies [81, 82]. On the STAR\*D study, mirtazapine was added to patients resistant to venlafaxine and was compared with switching to tranylcypromine (a MAOI). Both approaches had no different effects [83]. However, addition of mirtazapine to resistant patients requires additional

Bupropion, a noradrenergic/dopaminergic reuptake inhibitor, was studied in TRD patients [84]. Bupropion has a good tolerability and low side effect profile,

Buspirone, a serotonin (5-HT1A) receptor partial agonist, was studied in randomized, double-blind, placebo-controlled trials combined with an SSRI in patients with TRD [85]. Buspirone, at a dosage of 41 mg/day, was compared on the STAR\*D study with Bupropion SR at 267 mg/day, with similar effectiveness [44]. As with mirtazapine, bupropion addition is a popular practice as an enhancing maneuver,

For second-generation antipsychotics in patients with TRD, the following order was suggested based on benefit and a lower rate of adverse effects: aripiprazole, quetiapine, risperidone, and less frequently ziprasidone or olanzapine [58, 77, 86, 87]. Also, the use of brexpiprazole has been suggested if aripiprazole generates akathisia [88, 89]. The analysis of 16 studies comparing the addition of aripiprazole,

but additional studies are needed to justify its use on TRD patients.

and addition of a new one progressively over 1–2 weeks [58].

**44**

Augmentation of treatment with lithium was reported for the first time by De Montigny by combining it with tricyclic antidepressants [91]. Thereafter, multiple studies have demonstrated its efficacy. A meta-analysis of 10 placebo, controlled studies showed that the addition of lithium at a dose to 600–900 mg/day (plasma levels higher than 0.4 mEq/L) was superior to placebo [78, 92]. A meta-analysis of nine trials with 237 patients comparing lithium versus placebo found a higher response with lithium [84]. Lithium was effective in the augmentation with first- and secondgeneration antidepressants attached to a possible benefit in reducing suicide risk. A meta-analysis of nine studies with 234 patients, where double-blind trials with lithium and placebo on TRD patients were included, showed a broad effectiveness with this approach [93]. The authors concluded that it should be given for no less than 7 days at dose of 600–800 mg/day [93]. An analysis of the literature reviewing 12 randomized studies on lithium augmentation of SSRIs or atypical antipsychotic drug therapy found no statistical difference that favors the use of one approach or the other [94].

#### *2.4.1.10 Thyroid hormone*

Thyroid hormone, in particular T3, has been used as an augmenting agent since the 1960s [95]. The usual dose of T3 in the form of liothyronine is 25–50 pg and with thyroxine (T4) is 150 pg. An initial meta-analysis with T3 showed effectiveness against placebo [79]. Subsequent studies, however, have shown limited evidence of its effectiveness. A meta-analysis with four randomized studies with 95 patients who did not respond to tricyclic antidepressants compared augmentation with T3 versus placebo or T4 showed response in 53% patients who received T3 but had not statistical difference with placebo [79]. However, T3 augmentation is not very popular in the UK nor in the USA [96].

#### *2.4.1.11 Repetitive transcranial magnetic stimulation*

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive technique in which a sequence of high-intensity magnetic pulses is used to stimulate cortical neurons to treat neuropsychiatric disorders including major depressive disorder

[97]. This technique may be ambulatory, can be added to the current antidepressant treatment, and has good tolerability. Initial systematic reviews on mixed populations of depressed patients that included non-resistant patients supported their use on TRD patients [98–103]. A meta-analysis of 24 trials that included 1092 patients who underwent rTMS and sham conditions showed rTMS was superior in clinical improvement of patients with TRD. The response and remissions were 25 and 17% and 9 and 6% for the rTMS and sham conditions, respectively [104]. Short duration rTMS (1–4 weeks) has an evident antidepressant effect on TRD patients and is well tolerated. Nevertheless, remission rates and responses with rTMS are low and it is unknown if there is a sustained effect. Not known is whether effects of TMS are sustained over time and its speed of onset [104].

#### *2.4.1.12 Psychotherapy*

Addition of CBT usually helps TRD patients, as demonstrated by multiple randomized studies [105–107]. In a randomized 1-year study with CBT (12–18 sessions), it was observed that remission occurred more on CBT group of patients (28%) than in patients who did not receive it (15%). In another study, depressive symptoms were minor on a self-report 40 months after patients received CBT [108]. A 12-week study compared citalopram plus 16-session CBT with citalopram plus additional pharmacological approaches such as bupropion or buspirone in 182 ambulatory patients resistant to citalopram [109]. The number of patients who achieved remission was similar (23 and 33%). A 12-week study that compared nefazodone treatment with 16- to 20-session CBT versus nefazodone alone on 446 ambulatory patients with chronic depression (medium of 8 years) showed remission in more patients undergoing the combination (48 versus 29%) [110]. In hospitalized patients with severe depression, combination therapy is a common practice and its effectiveness is clear. A 12-week study that compares CBT and pharmacotherapy with pharmacotherapy alone in 20 hospitalized patients with chronic depression found a similar improvement [111]. An observational 12-week study with CBT added to pharmacotherapy in 24 hospitalized patients with chronic depression [112] found a 46% reduction in depressive symptoms. In TRD patients, other types of psychotherapy such as group, family, or interpersonal therapy have not been well studied.

#### *2.4.1.13 Other addition maneuvers*

Several addition maneuvers have been employed in TRD patients, such as lamotrigine combination, stimulants like methylphenidate, modafinil, and pindolol among others. A meta-analysis which included 10 studies with 289 patients undergoing lamotrigine treatment concluded that this drug had little effect on non-bipolar TRD patients [113]. Controlled studies evaluating placebo versus methylphenidate have been negative despite its regular use [114]. Modafinil did not show a sustained effect in two controlled studies. However, a subsequent retrospective analysis suggests that modafinil may help TRD patients with fatigue and somnolence [115]. Pindolol, a non-selective beta-adrenergic antagonistic with effect in the 5-HT1A auto-receptor has shown negative results against placebo on TRD patients [116]. N-methyl-D-aspartate (NMDA) receptor acting drugs like memantine, ketamine, and riluzole have been studied. Controlled studies with memantine, an NMDAreceptor antagonist, have been negative [117]. Ketamine, an NMDA-receptor antagonist anesthetic, has shown positive antidepressant results in a controlled study against placebo in patients with TRD [118]. Riluzole, a putative glutamate release inhibitor used in the treatment of amyotrophic lateral sclerosis, did not show effectiveness on a controlled study to prevent relapse after ketamine use [119].

**47**

*Resistant Depression*

*DOI: http://dx.doi.org/10.5772/intechopen.82568*

be more effective in women than in men [125].

*2.4.2 Studies comparing switching versus augmentation maneuvers*

Multiple guidelines suggest how to use augmentation or switching maneuvers

Various studies show that augmentation or switching maneuvers are equally efficient. Thus, multiple evaluations reviewing placebo-controlled randomized studies regarding augmentation and switching approaches show similar results [76]. The medium rate of remission with augmentation was 27% and switching was 22%, with response rates (reduction of 50% or more of the symptoms) of 38 and 40%, respectively [122]. A prospective study with citalopram on two groups of 269 patients who preferred augmentation with bupropion or buspirone to switching citalopram to bupropion, sertraline, or venlafaxine had a similar remission. A randomized study with 375 TRD patients, where several treatments were assigned, including five augmentations and two switching options [123, 124] showed similar results with 37 and 41% for each strategy. On the other hand, in a group with 1522 patients (85% men), almost 50% of them undergoing post-traumatic disorder, and who continued severely depressed after the first course of treatment with an antidepressant, almost all of them on psychotherapy, the augmentation approach with aripiprazole (5–15 mg/day) or bupropion (300–400 mg/day) was slightly superior to switching antidepressants to bupropion as monotherapy [75]. Remission was achieved in 29% of the patients with aripiprazole augmentation, 27% with bupropion augmentation, and 22% with switching to bupropion. Surveillance over 24 months of the remitted patients (n = 396) showed that approximately 25% of the patients in each group relapsed. There were more adverse effects in the aripiprazole group [75]. Other studies show that augmentation approach with aripiprazole may

With patients not tolerating the antidepressant dose, it is preferable to switch antidepressants. While there is evidence that suggests that augmentation is somehow superior to switching antidepressants, the decision should be discussed with the patient. Clinical criteria would be that patients who have had partial benefit from the initial antidepressant and have few adverse effects may prefer an augmentation approach and those with less improvement and more adverse effects might prefer switching medication. However, in patients resistant to a second treatment, there is no evidence that shows how many approaches should be done before considering change of treatment. Authors suggest 1–3 trials before switching [58, 74]. Changing medications has the advantage of achieving a better compliance to treatment than when more than one medication is used [126] adding a lower risk of adverse effects, pharmacologic interactions, and costs. A study evaluated 48 trials that included 6654 patients. A comparison was made between randomized studies, which compared 11 agents used on augmentation approaches: atypical antipsychotics (aripiprazole, olanzapine, quetiapine, and risperidone), antidepressants (bupropion, buspirone), lithium, thyroid hormone, methylphenidate, pindolol, and lamotrigine [87]. The studies analyzed were compared between them or placebo in patients with TRD and the proportion of patients who responded to treatment was defined as primary effectiveness. The analysis showed that primary effectiveness was higher with quetiapine, aripiprazole, thyroid hormone, and lithium in relation to placebo, but even higher for the former two in the sensibility analysis. There were no differences regarding discontinuation rate and adverse effects (acceptability) for these treatments [87]. Quetiapine, olan-

zapine, aripiprazole, and lithium were less well tolerated than placebo [87].

(The American Psychiatric Association, United Kingdom National Institute of Health and Clinical Excellence guidelines among others) [28, 66, 120, 121]. However, few randomized studies comparing the effectiveness of these maneuvers on TRD patients have been performed and most of them do not differ between those patients with little or no benefit from those who improve partially.

*Antidepressants - Preclinical, Clinical and Translational Aspects*

sustained over time and its speed of onset [104].

family, or interpersonal therapy have not been well studied.

Several addition maneuvers have been employed in TRD patients, such as lamotrigine combination, stimulants like methylphenidate, modafinil, and pindolol among others. A meta-analysis which included 10 studies with 289 patients undergoing lamotrigine treatment concluded that this drug had little effect on non-bipolar TRD patients [113]. Controlled studies evaluating placebo versus methylphenidate have been negative despite its regular use [114]. Modafinil did not show a sustained effect in two controlled studies. However, a subsequent retrospective analysis suggests that modafinil may help TRD patients with fatigue and somnolence [115]. Pindolol, a non-selective beta-adrenergic antagonistic with effect in the 5-HT1A auto-receptor has shown negative results against placebo on TRD patients [116]. N-methyl-D-aspartate (NMDA) receptor acting drugs like memantine, ketamine, and riluzole have been studied. Controlled studies with memantine, an NMDAreceptor antagonist, have been negative [117]. Ketamine, an NMDA-receptor antagonist anesthetic, has shown positive antidepressant results in a controlled study against placebo in patients with TRD [118]. Riluzole, a putative glutamate release inhibitor used in the treatment of amyotrophic lateral sclerosis, did not show effectiveness on a controlled study to prevent relapse after ketamine use [119].

*2.4.1.13 Other addition maneuvers*

*2.4.1.12 Psychotherapy*

[97]. This technique may be ambulatory, can be added to the current antidepressant treatment, and has good tolerability. Initial systematic reviews on mixed populations of depressed patients that included non-resistant patients supported their use on TRD patients [98–103]. A meta-analysis of 24 trials that included 1092 patients who underwent rTMS and sham conditions showed rTMS was superior in clinical improvement of patients with TRD. The response and remissions were 25 and 17% and 9 and 6% for the rTMS and sham conditions, respectively [104]. Short duration rTMS (1–4 weeks) has an evident antidepressant effect on TRD patients and is well tolerated. Nevertheless, remission rates and responses with rTMS are low and it is unknown if there is a sustained effect. Not known is whether effects of TMS are

Addition of CBT usually helps TRD patients, as demonstrated by multiple randomized studies [105–107]. In a randomized 1-year study with CBT (12–18 sessions), it was observed that remission occurred more on CBT group of patients (28%) than in patients who did not receive it (15%). In another study, depressive symptoms were minor on a self-report 40 months after patients received CBT [108]. A 12-week study compared citalopram plus 16-session CBT with citalopram plus additional pharmacological approaches such as bupropion or buspirone in 182 ambulatory patients resistant to citalopram [109]. The number of patients who achieved remission was similar (23 and 33%). A 12-week study that compared nefazodone treatment with 16- to 20-session CBT versus nefazodone alone on 446 ambulatory patients with chronic depression (medium of 8 years) showed remission in more patients undergoing the combination (48 versus 29%) [110]. In hospitalized patients with severe depression, combination therapy is a common practice and its effectiveness is clear. A 12-week study that compares CBT and pharmacotherapy with pharmacotherapy alone in 20 hospitalized patients with chronic depression found a similar improvement [111]. An observational 12-week study with CBT added to pharmacotherapy in 24 hospitalized patients with chronic depression [112] found a 46% reduction in depressive symptoms. In TRD patients, other types of psychotherapy such as group,

**46**

#### *2.4.2 Studies comparing switching versus augmentation maneuvers*

Multiple guidelines suggest how to use augmentation or switching maneuvers (The American Psychiatric Association, United Kingdom National Institute of Health and Clinical Excellence guidelines among others) [28, 66, 120, 121]. However, few randomized studies comparing the effectiveness of these maneuvers on TRD patients have been performed and most of them do not differ between those patients with little or no benefit from those who improve partially.

Various studies show that augmentation or switching maneuvers are equally efficient. Thus, multiple evaluations reviewing placebo-controlled randomized studies regarding augmentation and switching approaches show similar results [76]. The medium rate of remission with augmentation was 27% and switching was 22%, with response rates (reduction of 50% or more of the symptoms) of 38 and 40%, respectively [122]. A prospective study with citalopram on two groups of 269 patients who preferred augmentation with bupropion or buspirone to switching citalopram to bupropion, sertraline, or venlafaxine had a similar remission. A randomized study with 375 TRD patients, where several treatments were assigned, including five augmentations and two switching options [123, 124] showed similar results with 37 and 41% for each strategy. On the other hand, in a group with 1522 patients (85% men), almost 50% of them undergoing post-traumatic disorder, and who continued severely depressed after the first course of treatment with an antidepressant, almost all of them on psychotherapy, the augmentation approach with aripiprazole (5–15 mg/day) or bupropion (300–400 mg/day) was slightly superior to switching antidepressants to bupropion as monotherapy [75]. Remission was achieved in 29% of the patients with aripiprazole augmentation, 27% with bupropion augmentation, and 22% with switching to bupropion. Surveillance over 24 months of the remitted patients (n = 396) showed that approximately 25% of the patients in each group relapsed. There were more adverse effects in the aripiprazole group [75]. Other studies show that augmentation approach with aripiprazole may be more effective in women than in men [125].

With patients not tolerating the antidepressant dose, it is preferable to switch antidepressants. While there is evidence that suggests that augmentation is somehow superior to switching antidepressants, the decision should be discussed with the patient. Clinical criteria would be that patients who have had partial benefit from the initial antidepressant and have few adverse effects may prefer an augmentation approach and those with less improvement and more adverse effects might prefer switching medication. However, in patients resistant to a second treatment, there is no evidence that shows how many approaches should be done before considering change of treatment. Authors suggest 1–3 trials before switching [58, 74]. Changing medications has the advantage of achieving a better compliance to treatment than when more than one medication is used [126] adding a lower risk of adverse effects, pharmacologic interactions, and costs. A study evaluated 48 trials that included 6654 patients. A comparison was made between randomized studies, which compared 11 agents used on augmentation approaches: atypical antipsychotics (aripiprazole, olanzapine, quetiapine, and risperidone), antidepressants (bupropion, buspirone), lithium, thyroid hormone, methylphenidate, pindolol, and lamotrigine [87]. The studies analyzed were compared between them or placebo in patients with TRD and the proportion of patients who responded to treatment was defined as primary effectiveness. The analysis showed that primary effectiveness was higher with quetiapine, aripiprazole, thyroid hormone, and lithium in relation to placebo, but even higher for the former two in the sensibility analysis. There were no differences regarding discontinuation rate and adverse effects (acceptability) for these treatments [87]. Quetiapine, olanzapine, aripiprazole, and lithium were less well tolerated than placebo [87].

A randomized 8-week study on 140 TRD patients with paroxetine plus risperidone, paroxetine plus trazodone, and paroxetine plus thyroid hormone showed similar remission rates of 27, 43, and 38%, respectively [123]. A 6-week randomized open study that compared adding quetiapine (target dose 300 mg/day) with adding lithium (target plasma concentration from 0.6 to 1.2 mmol/L) in 450 resistant patients got a similar remission rate of 32 and 27%, respectively [127].

A meta-analysis with 48 randomized trials (n > 6000 depressed patients) in which efficiency of augmentation agents was evaluated using results from comparisons between drugs (on head to head trials), as well as indirect comparisons of the drugs through their relative effects with a common comparator (typically a placebo) [123]. The response (reduction equal or higher than 50%) or remission was more frequent when aripiprazole, lithium, olanzapine, quetiapine, risperidone, or thyroid hormone (T3 or T4) was added, compared to placebo; results from each one were comparable. Discontinuation due to adverse effects was higher with aripiprazole, lithium, olanzapine, and quetiapine than with placebo.

#### *2.4.3 Promising new treatments*

#### *2.4.3.1 Acetylcholine receptor acting drugs*

Medications that act on the cholinergic system seem promising in the treatment of TRD patients. Controlled studies versus placebo with intravenous scopolamine (a muscarinic antagonist) in TRD patients showed promising results [128]. Mecamylamine, a nAChR antagonist added to citalopram, was also superior to placebo [129]. Other drugs like mecamylamine, S-mecamylamine, and varenicline are currently in a preliminary stage of study in depressive patients [129, 130].

#### *2.4.3.2 N-methyl-D-aspartate (NMDA) acting drugs*

Ketamine, an NMDA-receptor antagonist, has shown antidepressant effects in TRD patients in a controlled study versus placebo [118]. However, ketamine, a dissociative anesthetic administration which complicates TRD patient treatment due to its route of administration (intravenous), requires hospitalization and consultation with an anesthesiologist. The rapid effects of ketamine usually disappear in 4–6 days. Also, it is possible that patients who improve on ketamine require a longterm course of maintenance. Ketamine has been given intranasal, or by sublingual delivery. Lapidus et al. [131] compared intranasal administration of ketamine 50 mg and placebo in 20 TRD patients. Patients improved at 24 h, but not at 72 h after administration. Recent studies are currently researching intranasal administration of esketamine, the S-enantiomer of racemic ketamine on TRD patients. Initial results are very promising [132]. If accepted, esketamine would enter the list of enhancement approaches for TRD patients.

Deep brain stimulation, vagus nerve stimulation, and neurosurgical lesions have also been evaluated in different studies as therapeutic options in highly resistant TRD patients [133].

#### **2.5 Neurobiological aspects of resistant depression**

Most antidepressants act by modulating serotonin, noradrenaline, and dopamine neurotransmission, but other neurotransmission routes seem to be involved such as cholinergic, glutamatergic, neuropeptides, and neuromodulators among others. The complex neurotransmission systems are prone to failure in the shortor long-term, blocking antidepressant action. Besides, different antidepressant

**49**

TRD [164].

antidepressant treatment is considered.

*Resistant Depression*

*DOI: http://dx.doi.org/10.5772/intechopen.82568*

been associated with low SSRI response.

treatments seem to exert action by different mechanisms modulating different cerebral regions [134]. Genetic variants may explain up to 42% of antidepressant response [135]. Genetic polymorphisms for cytochrome P-450 (CYP) enzymes may lead to a reduction on enzyme activity of the CYP2D6 or CYP3A4 variants, leading to intolerance to antidepressants on high plasmatic levels [136, 137]. Some patients are rapid metabolizers, resulting in low plasmatic levels at standard doses of antidepressants, leading to resistance. Evaluation of these genetic variants is accessible with pharmacogenetic studies of antidepressants. Other resistance genetic variants may be related to p-glycoprotein (p-gp), also known as the ABCB1 drug multiresistance gene [138]. Besides this, other polymorphic variants have been associated with response to antidepressants. In the case of serotonin 2A gene (HTR2A), both coding and noncoding polimorphisms have been associated to low SSRIs response [139–141]. Furthermore, single nucleotid polymorphisms (SNPs) of the genes for brain-derived neurotrophic factor (BDNF) [142, 143], the norepinephrine transporter [144], tryptophan hydroxylase 2 [145, 146], corticotrophin releasing hormone receptor 1 [147], the glucocorticoid receptor [148, 149], and the common promoter polymorphism of the serotonin transporter gene [150–155] have

It has been published that the activation of the immune system and neuroinflammation represent a primary event in the pathophysiology of TRD [156–158] and that the effect of NSAID may increase the effect of antidepressants [159].

Finally, the catecholaminergic hypothesis of depression [160, 161], which associates depression with low levels of neurotransmitters, was accepted to explain not only the neurobiochemistry of depression, but also the effect of antidepressant drugs. This hypothesis postulates that, in depression, the function of the dopamine, noradrenaline, and indolamine serotonin monoamines is decreased. In support of this, different studies have shown changes in plasma, urine, and cerebrospinal fluid concentrations of these neurotransmitters and their metabolites, changes in the density of neuroreceptors in platelets and neurons, flattened curves in neuroendocrine challenges and also early relapses with the blockade of restriction enzymes for neurotransmitter synthesis in patients who had achieved depression remission with antidepressant treatment [162]. The existence of subtypes of depression, where noradrenergic, serotoninergic, or dopaminergic negative balance is predominant, has been also postulated. Patients with these subtypes of depression hypothetically would respond better to antidepressant drugs with noradrenergic, serotoninergic and dopaminergic effects. Unfortunately, clinical studies on the effect of antidepressants with different mechanisms of action show contradicting results, and today there are not clear clinical or biological parameters to predict the results of different antidepressant treatments [163]. It should be noted that any theory about the cause of TRD would be simplistic including that the deficit of a single neurotransmitter, genetic, or immune system and neuroinflammation responses would be present in most TRD patients. However, knowing if there are groups of patients that may respond better to drugs with different mechanisms of action continues to be important for the treatment of patients with

It has been suggested that, in the selection of an antidepressant drug, the clinician must observe the overall response of the patient with major depression [165]. Also, in the selection of an antidepressant drug, the clinician must observe the possible relationship between the drug's biochemical effect and its effects on specific symptoms but also on adverse events. This became more relevant when a drug or group of drugs have failed to improve the patient and a new one has to be supplied, when adverse events force treatment change or when augmentation or change of

*Antidepressants - Preclinical, Clinical and Translational Aspects*

A randomized 8-week study on 140 TRD patients with paroxetine plus risperidone, paroxetine plus trazodone, and paroxetine plus thyroid hormone showed similar remission rates of 27, 43, and 38%, respectively [123]. A 6-week randomized open study that compared adding quetiapine (target dose 300 mg/day) with adding lithium (target plasma concentration from 0.6 to 1.2 mmol/L) in 450 resistant

A meta-analysis with 48 randomized trials (n > 6000 depressed patients) in which efficiency of augmentation agents was evaluated using results from comparisons between drugs (on head to head trials), as well as indirect comparisons of the drugs through their relative effects with a common comparator (typically a placebo) [123]. The response (reduction equal or higher than 50%) or remission was more frequent when aripiprazole, lithium, olanzapine, quetiapine, risperidone, or thyroid hormone (T3 or T4) was added, compared to placebo; results from each one were comparable. Discontinuation due to adverse effects was higher with aripipra-

Medications that act on the cholinergic system seem promising in the treatment of TRD patients. Controlled studies versus placebo with intravenous scopolamine (a muscarinic antagonist) in TRD patients showed promising results [128]. Mecamylamine, a nAChR antagonist added to citalopram, was also superior to placebo [129]. Other drugs like mecamylamine, S-mecamylamine, and varenicline are currently in a preliminary stage of study in depressive patients [129, 130].

Ketamine, an NMDA-receptor antagonist, has shown antidepressant effects in TRD patients in a controlled study versus placebo [118]. However, ketamine, a dissociative anesthetic administration which complicates TRD patient treatment due to its route of administration (intravenous), requires hospitalization and consultation with an anesthesiologist. The rapid effects of ketamine usually disappear in 4–6 days. Also, it is possible that patients who improve on ketamine require a longterm course of maintenance. Ketamine has been given intranasal, or by sublingual delivery. Lapidus et al. [131] compared intranasal administration of ketamine 50 mg and placebo in 20 TRD patients. Patients improved at 24 h, but not at 72 h after administration. Recent studies are currently researching intranasal administration of esketamine, the S-enantiomer of racemic ketamine on TRD patients. Initial results are very promising [132]. If accepted, esketamine would enter the list of

Deep brain stimulation, vagus nerve stimulation, and neurosurgical lesions have also been evaluated in different studies as therapeutic options in highly resistant

Most antidepressants act by modulating serotonin, noradrenaline, and dopamine neurotransmission, but other neurotransmission routes seem to be involved such as cholinergic, glutamatergic, neuropeptides, and neuromodulators among others. The complex neurotransmission systems are prone to failure in the shortor long-term, blocking antidepressant action. Besides, different antidepressant

patients got a similar remission rate of 32 and 27%, respectively [127].

zole, lithium, olanzapine, and quetiapine than with placebo.

*2.4.3 Promising new treatments*

*2.4.3.1 Acetylcholine receptor acting drugs*

*2.4.3.2 N-methyl-D-aspartate (NMDA) acting drugs*

enhancement approaches for TRD patients.

**2.5 Neurobiological aspects of resistant depression**

TRD patients [133].

**48**

treatments seem to exert action by different mechanisms modulating different cerebral regions [134]. Genetic variants may explain up to 42% of antidepressant response [135]. Genetic polymorphisms for cytochrome P-450 (CYP) enzymes may lead to a reduction on enzyme activity of the CYP2D6 or CYP3A4 variants, leading to intolerance to antidepressants on high plasmatic levels [136, 137]. Some patients are rapid metabolizers, resulting in low plasmatic levels at standard doses of antidepressants, leading to resistance. Evaluation of these genetic variants is accessible with pharmacogenetic studies of antidepressants. Other resistance genetic variants may be related to p-glycoprotein (p-gp), also known as the ABCB1 drug multiresistance gene [138]. Besides this, other polymorphic variants have been associated with response to antidepressants. In the case of serotonin 2A gene (HTR2A), both coding and noncoding polimorphisms have been associated to low SSRIs response [139–141]. Furthermore, single nucleotid polymorphisms (SNPs) of the genes for brain-derived neurotrophic factor (BDNF) [142, 143], the norepinephrine transporter [144], tryptophan hydroxylase 2 [145, 146], corticotrophin releasing hormone receptor 1 [147], the glucocorticoid receptor [148, 149], and the common promoter polymorphism of the serotonin transporter gene [150–155] have been associated with low SSRI response.

It has been published that the activation of the immune system and neuroinflammation represent a primary event in the pathophysiology of TRD [156–158] and that the effect of NSAID may increase the effect of antidepressants [159].

Finally, the catecholaminergic hypothesis of depression [160, 161], which associates depression with low levels of neurotransmitters, was accepted to explain not only the neurobiochemistry of depression, but also the effect of antidepressant drugs. This hypothesis postulates that, in depression, the function of the dopamine, noradrenaline, and indolamine serotonin monoamines is decreased. In support of this, different studies have shown changes in plasma, urine, and cerebrospinal fluid concentrations of these neurotransmitters and their metabolites, changes in the density of neuroreceptors in platelets and neurons, flattened curves in neuroendocrine challenges and also early relapses with the blockade of restriction enzymes for neurotransmitter synthesis in patients who had achieved depression remission with antidepressant treatment [162]. The existence of subtypes of depression, where noradrenergic, serotoninergic, or dopaminergic negative balance is predominant, has been also postulated. Patients with these subtypes of depression hypothetically would respond better to antidepressant drugs with noradrenergic, serotoninergic and dopaminergic effects. Unfortunately, clinical studies on the effect of antidepressants with different mechanisms of action show contradicting results, and today there are not clear clinical or biological parameters to predict the results of different antidepressant treatments [163]. It should be noted that any theory about the cause of TRD would be simplistic including that the deficit of a single neurotransmitter, genetic, or immune system and neuroinflammation responses would be present in most TRD patients. However, knowing if there are groups of patients that may respond better to drugs with different mechanisms of action continues to be important for the treatment of patients with TRD [164].

It has been suggested that, in the selection of an antidepressant drug, the clinician must observe the overall response of the patient with major depression [165]. Also, in the selection of an antidepressant drug, the clinician must observe the possible relationship between the drug's biochemical effect and its effects on specific symptoms but also on adverse events. This became more relevant when a drug or group of drugs have failed to improve the patient and a new one has to be supplied, when adverse events force treatment change or when augmentation or change of antidepressant treatment is considered.

#### **3. Conclusions**

Once resistance to treatment with two drugs with different action mechanisms has been established, the next best therapeutic decision is *terra ignota* because there is not enough scientific information available to validate which steps are to follow: whether change treatment, adding an antidepressant, "buster therapies" like addition of lithium, thyroid hormone or stimulants, add atypical antipsychotics, rTMS or employment of newly treatments such as ketamine, or ECT. In the evaluation stages for the treatment of a patient with TRD it is important to make an evaluation and reassessment of the case. This includes confirming the diagnosis of major depressive disorder, making the differential diagnoses of bipolar depression or other forms of resistant depression such as secondary to other medical issues, drugs, etc. Medical and psychiatric comorbidities, as well as depression severity should be assessed. Also, a detailed clinical history on antidepressant use should be performed. The application of diagnostic tools or evaluation scales is relevant.

Despite of its importance and frequency, there is no consensus over what TRD is. Advances have been made over assessment tools to evaluate resistance to treatment. However, there is no consensus over which is the best stratification system for TRD. There is a lack of research that validates which treatment approaches may be more effective and which ones should be used in the different stages in the management of a resistant patient. Unfortunately, advances over neurobiology of depression cannot be transferred yet to a clinical level to help the physician choose the best treatment for a patient with major depression and even less so for a TRD patient [163, 164]. In patients who have an inadequate response to the first line of treatment, the clinician has many options to change the treatment, but if the second approach fails, other approaches seem to be equally effective in according to what is published on the literature and there are no clear guidelines that support one or the other. This outlook is discouraging for patients and physicians who are on trial and error until they find something that helps the patient. Future research on TRD patients should be centered on neurobiological factors involved in the development of the resistance including pharmacogenetics. Without the development of techniques that help us predict which factors are related to this phenomenon, treatment of TRD patients will continue to be insufficient.

#### **Acknowledgements**

The author wishes to thank the Department of Psychiatry of the University Hospital UANL and the INFOSAME for its support in the preparation of this manuscript.

#### **Conflict of interest**

Dr. Jose Alfonso Ontiveros has received research grants from AstraZeneca, Glaxo Smith Kline, Eli Lilly, Servier, Wyeth, Lundbeck, Janssen-Cilag, Pfiser, and Sunovion.

**51**

**Author details**

Mexico

Jose Alfonso Ontiveros

Department of Psychiatry, Autonomous University of Nuevo Leon, Monterrey,

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: ontiverosalf@gmail.com

provided the original work is properly cited.

*Resistant Depression*

*DOI: http://dx.doi.org/10.5772/intechopen.82568*

*Resistant Depression DOI: http://dx.doi.org/10.5772/intechopen.82568*

*Antidepressants - Preclinical, Clinical and Translational Aspects*

Once resistance to treatment with two drugs with different action mechanisms has been established, the next best therapeutic decision is *terra ignota* because there is not enough scientific information available to validate which steps are to follow: whether change treatment, adding an antidepressant, "buster therapies" like addition of lithium, thyroid hormone or stimulants, add atypical antipsychotics, rTMS or employment of newly treatments such as ketamine, or ECT. In the evaluation stages for the treatment of a patient with TRD it is important to make an evaluation and reassessment of the case. This includes confirming the diagnosis of major depressive disorder, making the differential diagnoses of bipolar depression or other forms of resistant depression such as secondary to other medical issues, drugs, etc. Medical and psychiatric comorbidities, as well as depression severity should be assessed. Also, a detailed clinical history on antidepressant use should be performed. The application of diagnostic tools or

Despite of its importance and frequency, there is no consensus over what TRD is. Advances have been made over assessment tools to evaluate resistance to treatment. However, there is no consensus over which is the best stratification system for TRD. There is a lack of research that validates which treatment approaches may be more effective and which ones should be used in the different stages in the management of a resistant patient. Unfortunately, advances over neurobiology of depression cannot be transferred yet to a clinical level to help the physician choose the best treatment for a patient with major depression and even less so for a TRD patient [163, 164]. In patients who have an inadequate response to the first line of treatment, the clinician has many options to change the treatment, but if the second approach fails, other approaches seem to be equally effective in according to what is published on the literature and there are no clear guidelines that support one or the other. This outlook is discouraging for patients and physicians who are on trial and error until they find something that helps the patient. Future research on TRD patients should be centered on neurobiological factors involved in the development of the resistance including pharmacogenetics. Without the development of techniques that help us predict which factors are related to this phenomenon, treatment

The author wishes to thank the Department of Psychiatry of the University Hospital UANL and the INFOSAME for its support in the preparation of this

Dr. Jose Alfonso Ontiveros has received research grants from AstraZeneca, Glaxo Smith Kline, Eli Lilly, Servier, Wyeth, Lundbeck, Janssen-Cilag, Pfiser, and

**3. Conclusions**

evaluation scales is relevant.

of TRD patients will continue to be insufficient.

**Acknowledgements**

**Conflict of interest**

manuscript.

Sunovion.

**50**

### **Author details**

Jose Alfonso Ontiveros Department of Psychiatry, Autonomous University of Nuevo Leon, Monterrey, Mexico

\*Address all correspondence to: ontiverosalf@gmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[17] Ruhe HG, Huyser J, Swinkels JA, Schene AH. Switching antidepressants after a first selective serotonin reuptake inhibitor in major depressive disorder: A systematic review. The Journal of Clinical Psychiatry. 2006;**67**(12):1836-1855

[18] Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: A STAR\*D report. The American Journal of Psychiatry. 2006;**163**(11):1905-1917

[19] O'Reardon JP, Amsterdam JD. Overview of treatment-resistant depression and its management. In: Amsterdam JD, Hornig M, Nierenberg AA, editors. Treatment-Resistant mood disorders. New York (NY): Cambridge University Press; 2001. pp. 30-45

[20] O'Reardon JP, Brunswick DJ, Amsterdam JD. Treatment-resistant depression in the age of serotonin: Evolving strategies. Current Opinion in Psychiatry. 2000;**13**:93-98

[21] Henricus G, Ruhé HG, Van Rooijen G, Spijker J, Peeters F, Schene A. Staging methods for treatment resistant depression. A systematic review. Journal of Affective Disorders. 2012;**137**:35-45

[22] Nemeroff CB. Prevalence and management of treatment-resistant depression. The Journal of Clinical Psychiatry. 2007;**68**(Suppl 8):17-25

[23] Trivedi MH, Kleiber BA. Using treatment algorithms for the affective management of treatment-resistant depression. Journal of Clinical Psychiatry. 2001;**62**(Suppl 18):25-29

[24] Keitner GI, Ryan CE, Solomon DA. Realistic expectations and a disease management model for depressed patients with persistent symptoms. The Journal of Clinical Psychiatry. 2006;**67**(9):1412-1421

[25] Keller MB, Shapiro RW, Lavori PW, Wolfe N. Recovery in major depressive disorder: Analysis with the life table and regression models. Archives of General Psychiatry. 1982;**39**(8):905-910

[26] Rush AJ. STAR\*D: What have we learned? The American Journal of Psychiatry. 2007;**164**:201

[27] Mueller TI, Keller MB, Leon AC, Solomon DA, Shea MT, Coryell W, et al. Recovery after 5 years of unremitting major depressive disorder. Archives of General Psychiatry. 1996;**53**(9):794-799

[28] Malhi GS, Adams D, Porter R, et al. Clinical practice recommendations for depression. Acta Psychiatrica Scandinavica. Supplementum. 2009;(439):8-26

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transcranial magnetic stimulation for treatment-resistant depression: A systematic review and metaanalysis. Canadian Journal of Psychiatry.

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of Psychiatry. 1969;**126**:457

2000;**23**(4):743-755

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2006;**8**(2):241-258

2001;**31**(7):1141-1146

2001;**35**(4):149-169

A meta-analysis of repetitive transcranial magnetic stimulation in the treatment of depression. Psychopharmacology Bulletin.

[96] Dorling CM. Antidepressant augmentation and combinations. Psychiatric Clinics of North America.

Nonpharmacological, somatic treatments of depression: Electroconvulsive therapy and novel brain stimulation modalities. Dialogues in Clinical Neuroscience.

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depression: Meta-analysis of placebo-controlled studies. Journal of Clinical Psychopharmacology.

1999;**19**(5):427-434

2014;**168**:269

**58**

controlled trial. The British Journal of Psychiatry. 2011;**199**:317

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trial. The Journal of Clinical Psychiatry. 2008;**69**(1):87-94

[115] Fava M, Thase ME, De Battista C. A multicenter, placebo-controlled study of modafinil augmentation in partial responders to selective serotonin reuptake inhibitors with persistent fatigue and sleepiness. The Journal of Clinical Psychiatry. 2005;**66**(1):85-93

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*Antidepressants - Preclinical, Clinical and Translational Aspects*

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2013;**73**:1156-1163

2008;**28**:340-344

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2006;**63**(10):1121-1129

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2004;**61**:877-889

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**60**

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Section 3

Preclinical and

Translational Studies

Section 3
