**2. Materials and methods**

Nowadays, free access to national and international reporting ADR databases allows investigating new signals to be aware of possible risks. One of them is VigiBase®, the unique World Health Organization (WHO) global database for suspected ADRs maintained by the Uppsala Monitoring Centre (UMC) since 1968. This database disposes of a free-user interface VigiAccess™ that allows us to search for all data coming from over 110 countries, undersigning a statement of the responsibility for the appropriate use and interpretation of data [7].

For the present study, reported data of all the ADRs related to the chemical subgroup of the Anatomical Therapeutic Chemical (ATC) Classification System C10AA "HMG CoA reductase inhibitors" known as statins were searched in VigiAccess™ [8]. Data below the first heading adverse drug reactions (ADRs) for each active ingredient of interest—atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, and pitavastatin—were extracted on October 2, 2019. Signals for cerivastatin—withdrawn in 2001—are included and analyzed as of contrast.

In this database, it is not possible to calculate the frequency of any ADR, but the data mining methodology, Bayesian confidence propagation neural network (BCPNN), can be used in these situations [9]. Nevertheless, this methodology is developed and used by the UMC as the WHO Collaborating Centre for International Drug Monitoring [10–12].

To detect signals of ADR, this method BCPNN was improved, by the UMC of the WHO with an extension to the multiple comparison settings. The calculated Bayesian estimator of false discovery rate (FDR) works like a p-value, offering a positive signal if FDR < 0.05 [13, 14].

An adaptation of this methodology can be plausible as same as other diverse methods can be trustworthy in global adverse drug reaction surveillance with a correct interpretation of the signals [15]. This one consists of contrasting all the ADRs of the ATC subgroups instead of all the pairs of ADR-drugs of the database. In this case, only the chemical subgroup C10AA "HMG CoA reductase inhibitors" [16] was considered in the analysis. This methodology approach has previously demonstrated robustness and consistency when all the ADR databases were applied to a specific group of drugs [17–19]. Details of the algorithm performed are reported (see Appendix 1).

All the positive signals among statins were obtained. Those related to mental disorders were extracted and grouped depending on the presence of the ADR in the summary of product characteristics (SPC) of each active ingredient implied and categorized according to high-level terms (HLTs) including preferred terms (PTs) of the Medical Dictionary for Regulatory Activities (MedDRA) [20], the standard terminology used in VigiAccess™.

The first aggrupation for statin positive signals obtained (FDR < 0.05 and Sp ≥ 0.99) was related to similar pathology following MedDRA, e.g., insomnia (that include general, middle, terminal, sleep disorder, and poor quality of sleep) and depression (that include general, major, depressed mood, and depressive symptoms) (see Appendices 2 and 3).

Finally, a ranking of positive signals for each statin is proposed as a list of priority ADR to further study.

The R® free software v3.4.1. R [21] and PhViD® Package v1.0.8 [22] were used to implement the methodology and to obtain positive signals. All the searches of evidence were made in the Medline database via Pubmed® [23].

## **3. Results**

The total of positive signals with FDR < 0.05 and Sp ≥ 0.99 were 493, being 47 out of them related to a mental disorder (or confounding central symptoms): seven for atorvastatin (14.9%), three for fluvastatin (6.4%), three for lovastatin (6.4%), three for pitavastatin (6.4%), five for pravastatin (10.6%), eight for rosuvastatin (17.0%), and 29 for simvastatin (29.8%). All the results of algorithms related to a mental disorder and other confounding central disorders observed are available (see Appendices 2 and 3).

Subgroups of positive signals were second stratified and summarized considering the presence/absence of ADR in the summary of product characteristics. Mental disorders detected and reported in technical factsheets were insomnia, depression, dementia, and nightmares (**Table 1**), and not reported disorders were anxiety, bipolar disorder, and psychotic or emotional disorders/symptoms (**Table 2**). Finally, other diverse symptoms were identified to a greater or lesser extent with mental affectation


*1, insomnia and related (general); 2, middle insomnia; 3, terminal insomnia; 4, sleep disorder; 5, poor quality sleep; 6, depression (general); 7, major depression, 8, depressed mood; 9, depressive symptoms; 10, amnesia; 11, dementia (general); 12, dementia Alzheimer's type; 13, memory impairment; 14, nightmares; 15, abnormal dreams; 16, daydreaming. Sensitivity* ≥*0.20.*

*\*Stated in the summaries of product characteristics (SPCs).*

#### **Table 1.**

*Positive signals (FDR < 0.05; specificity* ≥*0.99) for statins related to mental disorders reported as ADR in Vigiaccess™.*


*1, bilateral blindness; 2, unilateral blindness; 3, bilateral deafness; 4, unilateral deafness; 5, anosmia; 6, ageusia; 7, balance disorder; 8, diplopia; 9, visual impairment; 10, visual acuity reduced; 11, vision blurred; 12, sudden hearing loss; 13, tinnitus; 14, dysgeusia; 15: anxiety; 16, bipolar disorder; 17, bipolar I disorder; 18, psychiatric symptom; 19, psychotic disorder; 20, emotional disorder; 21, emotional distress; 22, complete; 23, attempt; 24, ideation; 25, behavior. Sensitivity* ≥*0.20.*

*\*Stated in the summaries of product characteristics (SPCs).*

#### **Table 2.**

*Other positive signals (FDR < 0.05; specificity* ≥*0.99) for statins related to central or other mental disorders reported as ADR in Vigiaccess™.*

such as impairment of senses (blindness, deafness, and vision blurred), and compromised life (suicide) (**Table 2**).

If we perform a list of positive signals (FDR < 0.05; specificity ≥0.99; and sensitivity ≥0.20 and < 0.20) not stated in the factsheets of each active ingredient, differences among drugs are detected (**Table 3**). These all are candidates to be deeply studied in clinical trials. In addition, in terms of the number of reports, the most relevant signals with the highest number of pair [active ingredient-ADR] reports were simvastatin-ageusia (85 reports) and rosuvastatin-unilateral deafness (21 reports). Less sensitive signals, but alarming, were the pairs simvastatin-ADR related to suicide (477 reports), pravastatin-affectation of senses (375 reports), atorvastatinaffectation of senses (693 reports), and lovastatin-complete suicide (50 reports).

There are three signals reported in SPCs with an elevated number of pairs of ADRdrug counted: atorvastatin-amnesia with 1360 reports and simvastatin-insomnia with 1210 (see Appendix 2) and for the withdrawn cerivastatin-anxiety 2767 (despite being withdrawn since 2001) (see Appendix 3).

The fact to include all the statins (also the withdrawn cerivastatin) and all the ADRs reported for statins acts as a contrast to the method used. Positive signals of ADR that lead to the withdrawal of cerivastatin (i.e., rhabdomyolysis and transaminases increased) and typical ADR related to statins (i.e., myalgia and myopathy) are also detected (see Appendix 4).

## **4. Discussion**

This is the first study of mental adverse drug reactions (ADRs) related to statins using neural networks based on the principles of Bayes law. Owing to there being no evidence of similar studies, not even with the classical Bayesian methodology BCPNN, it is necessary to review the background to establish a starting point to further investigation.


*Early Signal Detection: Data Mining of Mental Disorders with Statins DOI: http://dx.doi.org/10.5772/intechopen.105504*

#### **Table 3.**

*List of early positive signals of mental (or central related) disorders detected for each statin agent and proposed to priority clinical investigation.*

### **4.1 Positive mental disorders mainly presented as ADRs in SPCs**

### *4.1.1 Insomnia*

Some studies reported insomnia with a higher frequency for statins compared with all other drugs [24], but this risk of insomnia with statins seems to be not significant

for other studies of neuropsychiatric adverse effects of statins [25]. At the same time, multimethodological approaches using different algorithms and databases strongly suggest that statin use is associated with an increased risk for sleep disturbances including insomnia [26].

The situation of insomnia can lead to a loss of adherence to the treatment, more worrying in the elderly because they are less capable of sleeping correctly and can lead to polymedicate with sleep medicines [27].

In the present study, the positive signal of middle insomnia obtained with atorvastatin appears as the most relevant and already stated in SPCs, followed by signals also informed for fluvastatin, pravastatin, rosuvastatin, and simvastatin. For pitavastatin, the newest statin, middle insomnia is not studied individually or reported in SPCs; the signal obtained is positive with specificity and sensitivity.

The only statin without a positive signal of insomnia was lovastatin. This result is following a former clinical 5-year follow-up study where insomnia had a very low presence [28], but there is no other evidence found for the last 10 years about that.

The same situation of no recent evidence remains for all the rest of the statins, except for rosuvastatin information derived from the randomized controlled trial JUPITER, where the authors recommended monitoring patients on intensive therapy and performing adverse events trials for lipid-lowering agents [27].

In addition, simvastatin showed an elevated number of pairs of ADR-statin with 1210 events reported in the present research (see Appendix 2). This ADR is stated as very rare in their SPCs.

It would be interesting to dispose of a follow-up study to update the effect of insomnia with statins, special, lovastatin, and pitavastatin. If these last ones offer less generation of insomnia, they can be candidates for people—in special, the elderly with sleep disorders.

#### *4.1.2 Depression*

In the present analysis, there is a clear positive signal of simvastatin and major depression and less sensitivity but also positive for depressed mood and depressive symptoms. In SPCs, depression is reported as ADR with unknown frequency.

Initially, the relationship between depression and metabolic disturbance, such as dyslipidemia, seems not to be clear. It has been observed that the increased appetite in the context of a depressive episode—was the only symptom that was associated with metabolic (and inflammatory) markers [29]. The authors of this study considered that it could be a key feature of an immunometabolic form of depression.

In this sense, it looks like inadequate nutrition leading to higher levels of cholesterol can be derived from some types of depression. On the other hand, using a genetic-based approach, it showed an increased risk of depression during statin [25].

Besides, some authors analyzed the association between statin treatment and antidepressant use, and they conclude that it is unspecific (equivalent association between statins and most other drugs) and that the association between statin use and depression diagnoses is mediated by residual confounding, bias, or by downstream effects of the statin prescription (seeing a physician more often) [30].

#### *4.1.3 Memory impairment: dementia*

Owing to the widespread use of statins, the severity of cognitive dysfunction, and its high prevalence in older people, some authors reflected that the patient

#### *Early Signal Detection: Data Mining of Mental Disorders with Statins DOI: http://dx.doi.org/10.5772/intechopen.105504*

communications about possible cognitive impairment must be considered and evaluated appropriately, including after discontinuation of the statin [31].

In the present research, positive signals are observed about dementia, dementia Alzheimer's type, and memory impairment for atorvastatin and rosuvastatin, as well as amnesia for atorvastatin.

Some authors considered that much of the evidence supporting statins in the prevention of dementia and Alzheimer's disease are in persons exposed to statins at mid-life as opposed to late life [32]. They conclude that statins have an evident protective effect on cognition, related to the prevention of stroke and possible subsequent vascular dementia and preventing microvascular infarcts that lead to dementia without an acute stroke, and this idea is supported by others [32–34]. Other studies have demonstrated that the overall rate of cognitive decline was not different in statin users compared with never users [35]. Nevertheless, the American Academy of Neurology does not address statin use to prevent dementia [36].

Some studies are more skeptical, with good evidence that statins given in late life to people at risk of vascular disease do not prevent cognitive decline or dementia [37]. Vascular dementia is the second commonest cause of this condition, and the authors consider a biologically plausible influence of the role in cholesterol associated with dementia. There is evidence of both the statin and nonstatin lipid-lowering drugs that were strongly associated with acute memory loss in the first 30 days following exposure in users compared with nonusers but not when compared with each other [38].

There is a conflict to determine if the balance of effects of lipids and lipid-lowering therapy falls on the branch of preventing or treating dementia or generating more risk [39].

The condition of amnesia with atorvastatin deserves a separate mention. In the present study, a positive signal only for atorvastatin was obtained (1360 cases notified). It was stated as low frequent in the factsheets, and there is no recent publication found in humans about that.

#### *4.1.4 Dreams disorders: nightmares*

A growing body of evidence indicates that statins may have potentially negative effects on nervous-system-associated diseases, including myopathies, peripheral neuropathy, intracerebral hemorrhage, cognitive impairment, depression, sleep disorders, nightmares, hallucinations, and headache [40, 41].

In a case report of atorvastatin, the authors hypothesized that the nightmares could be a direct effect of the statin on the central nervous system; they did not know if it was due to a pharmacokinetic (CYP3A4) or pharmacodynamic interaction. However, they recommend that if nightmares appear, it could be easy to avoid stopping statins [42].

Dreams disorders, not a severe condition, could lead to aversion and loss of adherence to the treatment. In the present study, pravastatin and simvastatin presented positive signals for nightmares and abnormal dreams, and fluvastatin only for nightmares. Rosuvastatin showed a positive signal with high sensitivity for daydreaming. Nightmares are reported in SPCs of all the statins with signals. On the contrary, daydreaming is not reported and could be especially compromising in older people with cognitive or mobility dysfunction.

A follow-up study of these symptoms can lead to prescribing statins less related to dream disorders ADR as atorvastatin, lovastatin, and pitavastatin.
