**3.1 Lithium**

Bipolar disorder, BD, is characterized by the presence of one or more episodes of mania or, in mild cases, hypomania and additional depressive episodes, concomitants or alternants.

The cause is unknown, although recent studies suggest the presence of an imbalance between excitatory neurotransmitters, mainly glutamate, and inhibitors, principally GABA, as well as alterations in cation pumps, such as of sodium and of calcium, which would explain the pathogenesis of bipolar disorder and another pathologies as epilepsy (Brown & Sherwood 2006).

To explain the action mechanism of Lithium salts there are several proposals, being the most known:


Biomarkers and Therapeutic Drug Monitoring in Psychiatry 163

transmission of noradrenaline and dopamine associated with dysregulation of the hypothalamic-pituitary-adrenal axis , HPA, which is reflected by the alteration of the cortisol escape from suppression by dexamethasone in the Dexamethasone Suppression test, DEX test, and by the increased response of cortisol in the Dexamethasone-Suppressed Corticotropin-Releasing Hormone Stimulation Test, DEX-CRH test. The decrease in serotonergic transmission in the brain and increased secretion of cortisol in patients with major depression have reached the status of an axiom in textbooks, being the cortisol the biological key mediator through which the brain slows down serotonergic transmission that causes depression in vulnerable people (American Psychiatric Association 2000; Dinan,

Deregulation of the hypothalamic-pituitary-adrenal axis is present in a high rate among the patients with depression and its normalization, observed by the response to the DEX-CRH test, is verified when there is a good response to pharmacological treatment. Moreover, the serotonergic system interacts with the hypothalamic-pituitary-adrenal axis and, because of this, the stimulation of this axis can be used as a Surrogate Marker for the pharmacological action of the 5-HT agonist in the CNS (Cowen 1993, 1998; Gartside & Cowen 1990; Meltzer &

The reduced serotonergic neurotransmission is well known feature of the depression and therefore it is not surprising that SSRI drugs were the first line of treatment in depressive disorders. Plasma levels of Escitalopram and another SSRI drugs decrease the HPA-response in the DEX test and there is a good correlation between dose of the SSRI drug and decreasing of plasma cortisol. Cortisol values obtained by Nugent's test, can be used as a Biomarker or Surrogate Marker for dosage regimen calculation of antidepressant drugs that act on serotonergic regulation of the HPA axis. The SSRI drugs whose main action is the activation of serotonergic transmission, produce a decrease of plasma cortisol value obtained by Nugent`s test, in dose-dependent manner and can be used as surrogate marker of SERT-carrier occupation and 5-HT receptor activation by the Escitalopram and/or other SSRI drugs and to serve for their dosage regimen calculation (Bel & Artigas 1992; Berkenbosch et al 1987; Bosker et al 1994; Hsieh et al 2010; Ising et al 2005, 2007; Knorr et al 2011; Maes et al 1993; Meltzer

PK-PD mechanistic-model. Around 50-60% of patients with depression have an increased activity of the hypothalamic-pituitary-adrenal axis and altered its regulation by negative feedback. Escitalopram and other SSRI produce an up-regulation of CRH receptors in a dose-dependent manner that can be measured by Nuggent`s test and this can be used for

Once the steady-state and a pharmacological response, ranging between the 20-80% of maximal effect, is reached we can estimate the optimal dose required to achieve cortisol values of 9.0 ± 2.1 mcg/dl, its Clinical Surrogate Endpoint, using equation 2 (Lozano et al

Metabolic studies for Escitalopram /Citalopram indicate that CYP3A4 and CYP2C19 are the major isozymes involved in N-demethylation of Escitalopram /Citalopram. The alleles

1996; Goodwin & Post 1983; Noll 2006; Schnider et al 1996).

1985; Nordstrom & Farde 1998; Sasayama et al 2011; Schule et al 2009).

dosage regimen calculation of escitalopram and other SSRIs.

Maes 1994; Meltzer et al 1991).

**3.2.1 PK-PD model** 

2008a, 2011a).

**3.2.2 PK-PG model** 

All the pharmacological activity of lithium salts is carried out by the insolubilization of intracellular inorganic phosphate salts through the formation of inorganic lithium phosphates. These ones have much lower solubility than their sodium salts (eg the solubility of Li3PO4 in water is 0.03821 g/dL/20 ° C versus of the Na3PO4 that is 8.8 g/dL/25 º C), which leads to decrease the amount of intracellular inorganic soluble phosphates, Pi, causing, consequently, decrease in intracellular phosphate stored in organic compounds, Po, and slowdown all metabolic reactions that involve exchange of inorganic phosphates, mainly those using ATP but, also, those using another nucleotides with capacity for the storage of phosphates, as we know now , and affecting in a hierarchically manner to several intracellular pathways of activation and/or inhibition, being those of GSK and inositolphosphates, among other, the first to be affected (Lozano et al 2009a, 2010a,2010b).

In the case of the thyroid gland, lithium salts cause a dose-dependent decrease in serum free thyroxine, FT4, due to the very low solubility of inorganic lithium phosphates, formed in the interior of target cells by action of lithium, which leads to a decrease in the intracellular pH and in the tyrosine iodination reaction, pH dependent, with consequent decrease of the FT4 levels, because the iodination of phenols is a direct reaction of iodine, I2, on the phenolate ion, very sensitive to changes in pH, decreasing exponentially the rate of iodination when the pH does it (Kessler et al 2008; Lozano et al 2010a, 2010b; Taylor & Evans 1953).

#### **3.1.1 PK-PD model**

Mechanistic-model. We can use the FT4 levels in plasma as a biomarker for quantifying the intraneuronal concentration of Lithium and the dosage regimen calculation in the treatments of bipolar disorder with salts Lithium, increasing o decreasing the daily dosage to reach FT4 values, in the range of 1.02-1.08 ng/dL, its Clinical Surrogate Endpoint (Lozano et al 2010a, 2010b).

#### **3.1.2 PK-PG model**

Due to the Lithium elimination by glomerular filtration, the poblational analisys conducted by Kernel`s test has allowed us to detect two subpopulations related to serum creatinine and therefore with the Lithium Clearance, caused by the presence of MDR1 polymorphisms, altering the aldosterone level and therefore the Creatinine Clearance, obtaining from the application of the equation 2, the following equi-effective dose ratio:

$$\frac{\text{DOSE} \left(\text{genotype:will type}\right)}{\text{DOSE} \left(\text{genome:public type}\right)} = 1.5 - 2$$

(Lozano et al 2011b).

#### **3.1.3 PK-PG model**

Poblational analysis conducted by Kernel`s test has not detected any subpopulation.

#### **3.2 Escitalopram-SSRI**

Depression is a pathological alteration of mood, being Major Depressive disorder the most studied with a prevalence of 10-25%. Its complex origin, is attributed to a defective

All the pharmacological activity of lithium salts is carried out by the insolubilization of intracellular inorganic phosphate salts through the formation of inorganic lithium phosphates. These ones have much lower solubility than their sodium salts (eg the solubility of Li3PO4 in water is 0.03821 g/dL/20 ° C versus of the Na3PO4 that is 8.8 g/dL/25 º C), which leads to decrease the amount of intracellular inorganic soluble phosphates, Pi, causing, consequently, decrease in intracellular phosphate stored in organic compounds, Po, and slowdown all metabolic reactions that involve exchange of inorganic phosphates, mainly those using ATP but, also, those using another nucleotides with capacity for the storage of phosphates, as we know now , and affecting in a hierarchically manner to several intracellular pathways of activation and/or inhibition, being those of GSK and inositol-

phosphates, among other, the first to be affected (Lozano et al 2009a, 2010a,2010b).

the pH does it (Kessler et al 2008; Lozano et al 2010a, 2010b; Taylor & Evans 1953).

**3.1.1 PK-PD model** 

et al 2010a, 2010b).

**3.1.2 PK-PG model** 

(Lozano et al 2011b).

**3.1.3 PK-PG model** 

**3.2 Escitalopram-SSRI** 

In the case of the thyroid gland, lithium salts cause a dose-dependent decrease in serum free thyroxine, FT4, due to the very low solubility of inorganic lithium phosphates, formed in the interior of target cells by action of lithium, which leads to a decrease in the intracellular pH and in the tyrosine iodination reaction, pH dependent, with consequent decrease of the FT4 levels, because the iodination of phenols is a direct reaction of iodine, I2, on the phenolate ion, very sensitive to changes in pH, decreasing exponentially the rate of iodination when

Mechanistic-model. We can use the FT4 levels in plasma as a biomarker for quantifying the intraneuronal concentration of Lithium and the dosage regimen calculation in the treatments of bipolar disorder with salts Lithium, increasing o decreasing the daily dosage to reach FT4 values, in the range of 1.02-1.08 ng/dL, its Clinical Surrogate Endpoint (Lozano

Due to the Lithium elimination by glomerular filtration, the poblational analisys conducted by Kernel`s test has allowed us to detect two subpopulations related to serum creatinine and therefore with the Lithium Clearance, caused by the presence of MDR1 polymorphisms, altering the aldosterone level and therefore the Creatinine Clearance, obtaining from the

> DOSE genotype:wild type 1.5 2 DOSE genotype:polimorphic type

Poblational analysis conducted by Kernel`s test has not detected any subpopulation.

Depression is a pathological alteration of mood, being Major Depressive disorder the most studied with a prevalence of 10-25%. Its complex origin, is attributed to a defective

application of the equation 2, the following equi-effective dose ratio:

transmission of noradrenaline and dopamine associated with dysregulation of the hypothalamic-pituitary-adrenal axis , HPA, which is reflected by the alteration of the cortisol escape from suppression by dexamethasone in the Dexamethasone Suppression test, DEX test, and by the increased response of cortisol in the Dexamethasone-Suppressed Corticotropin-Releasing Hormone Stimulation Test, DEX-CRH test. The decrease in serotonergic transmission in the brain and increased secretion of cortisol in patients with major depression have reached the status of an axiom in textbooks, being the cortisol the biological key mediator through which the brain slows down serotonergic transmission that causes depression in vulnerable people (American Psychiatric Association 2000; Dinan, 1996; Goodwin & Post 1983; Noll 2006; Schnider et al 1996).

Deregulation of the hypothalamic-pituitary-adrenal axis is present in a high rate among the patients with depression and its normalization, observed by the response to the DEX-CRH test, is verified when there is a good response to pharmacological treatment. Moreover, the serotonergic system interacts with the hypothalamic-pituitary-adrenal axis and, because of this, the stimulation of this axis can be used as a Surrogate Marker for the pharmacological action of the 5-HT agonist in the CNS (Cowen 1993, 1998; Gartside & Cowen 1990; Meltzer & Maes 1994; Meltzer et al 1991).

The reduced serotonergic neurotransmission is well known feature of the depression and therefore it is not surprising that SSRI drugs were the first line of treatment in depressive disorders. Plasma levels of Escitalopram and another SSRI drugs decrease the HPA-response in the DEX test and there is a good correlation between dose of the SSRI drug and decreasing of plasma cortisol. Cortisol values obtained by Nugent's test, can be used as a Biomarker or Surrogate Marker for dosage regimen calculation of antidepressant drugs that act on serotonergic regulation of the HPA axis. The SSRI drugs whose main action is the activation of serotonergic transmission, produce a decrease of plasma cortisol value obtained by Nugent`s test, in dose-dependent manner and can be used as surrogate marker of SERT-carrier occupation and 5-HT receptor activation by the Escitalopram and/or other SSRI drugs and to serve for their dosage regimen calculation (Bel & Artigas 1992; Berkenbosch et al 1987; Bosker et al 1994; Hsieh et al 2010; Ising et al 2005, 2007; Knorr et al 2011; Maes et al 1993; Meltzer 1985; Nordstrom & Farde 1998; Sasayama et al 2011; Schule et al 2009).
