Quetiapine was first approved by the United States Food and Drug Administration (FDA) in 1997? for the treatment of acute episodes of schizophrenia in adults. Over time, the wide possibilities of the pharmacological properties of the drug, due to which in 2003? It was approved for the treatment of manic episodes in bipolar affective disorder (BAR), in 2006? for the treatment of depressive episodes with BAR, and in 2008? has been recommended as maintenance therapy for BAR (Hawkins et al., 2013; Sanford, 2011). Since 2009?
Quetiapine has been used as an adjunct in the treatment of major depressive disorder (MDD) in combination with antidepressants without FDA approval (Mauri et al., 2007). Currently, this drug is not registered indications (off-label) is used for mental disorders such as generalized anxiety disorders, as monotherapy for monopolar depression, with delirium, psychotic symptoms associated with dementia and obsessive-compulsive disorder. Thus, the range of Quetiapine use has gone far beyond that approved by the FDA.
The use of quetiapine in affective disorders has been reviewed in a large number of double-blind, randomized clinical trials (RCTs). Currently, quetiapine is one of the most commonly used drugs for bipolar and monopolar disorders (Lopez-Munoz et al., 2013).
The authors of the article conducted a thorough search in the PUBMED database of all RCTs published before December 2015? In which quetiapine IR or XR was used in patients with depressive episodes in bipolar and monopolar disorders. Among all the studies, RCTs were selected that meet the criteria for the analysis.
Pharmacokinetic Profile of Quetiapine
Quetiapine belongs to the group of preparations of dibenzothiazepine derivatives. Available in two forms: with immediate (IR) and prolonged (XR) release. With a single dose in therapeutic doses, the drug demonstrates linear kinetics with a half-life of about 7 hours. Both forms have the same bioavailability. At the same time, the peak plasma concentration in Quetiapine IR is 2 hours, and Quetiapine XR – 5 hours. Quetiapine XR is also characterized by a longer maintenance of high plasma concentrations. Therefore, to maintain therapeutic concentrations, it is possible to take the drug once a day, while Quetiapine IR should be taken 2 times a day (Mauri et al., 2007; Bui, 2013).
Quetiapine is metabolized in the liver to form various derivatives, and only 1?% Is excreted unchanged in the urine. N-dezalkilkvetiapin (norkvetiapin) is the most important metabolite of the drug. Norkvetiapin is formed by CYP3A4 isoenzymes of the cytochrome P450 system (Lopez-Munoz et al., 2013). Due to the lack of genetic polymorphism of CYP3A4, any differences in quetiapine metabolism associated with racial or genetic traits are unlikely. Nevertheless, some inducers (carbamazepine, phenytoin), which increase the amount of norkvetiapine, or inhibitors (ketoconazole, itraconazole, erythromycin, and fluvoxamine), which decrease its production, affect the activity of this isoenzyme (Winter et al., 2008; Prieto et al., 2010). In elderly patients and patients taking concomitant medications, pharmacokinetic variability was more pronounced in quetiapine than in norkvetiapin, hence the concentrations of norkvetiapin were more stable (Bakken et al., 2011).
The less significant metabolic pathway of quetiapine occurs through CYP2D6 to form 7-hydroxy-quetiapine, which is not supposed to have pharmacological activity (Fisher et al., 2012), and 7-hydroxy-dealkyl-quetiapine, which has pharmacological activity (Bakken et al., 2012). According to Mauri et al. (2007), the plasma concentrations of quetiapine are not high enough to determine its effect on the receptors or its clinical effects. According to scientists, the active metabolites of the drug are also responsible for its pharmacodynamic characteristics.
Pharmacodynamic profile of quetiapine
The main mechanism underlying the antipsychotic activity of quetiapine is the blockade of the dopamine D2 receptors of the mesolimbic nerve pathways. Both quetiapine and norkvetiapin have a moderate affinity for D1 and D2 receptors, and the former quickly dissociates with D2 receptors. This explains the need to receive sufficiently high doses of quetiapine for the development of antipsychotic effect (Altamura et al., 2012). However, quetiapine does not affect the regulation of the activity of these receptors, which explains the low level of development of tardive dyskinesia during prolonged therapy with this drug. In the nigrostrial and tuberoinfundibular dopaminergic nerve pathways, serotonin acts as an inhibitor due to its effect on 5HT2A receptors.
Quetiapine and norkvetiapin have a strong antagonistic effect on these receptors, which contributes to the release of dopamine and provides a low level of extrapyramidal side effects and hyperprolactinemia (Kapur et al., 2000). A large number of depressive symptoms, such as agedonia, psychomotor retardation, social exclusion and loss of motivation are the result of reduced dopamine neurotransmission in the prefrontal cortex. According to some scientists, norkvetiapin due to antagonism with 5HT2A – and 5HT2C-receptors promotes the release of dopamine in the prefrontal cortex and reduces the symptoms of depression in patients with affective disorders (Mundo et al., 2006).
Dopamine reuptake is carried out by a norepinephrine carrier protein. Quetiapine and norkvetiapin potentiate serotonergic transmission of nerve impulses, acting as partial 5HT1A receptor agonists, which are associated with antidepressant and anxiolytic effects. In particular, norkvetiapin has a high affinity for 5HT1A receptors, similar to buspirone and gepironom. Thus, it increases serotonergic neurotransmission in neurons of the brain stem seam, and also modulates the 5HT activity of the cortex and limbic system (Bjorkholm et al., 2013). Activating these receptors in the hippocampus, norkvetiapin affects the increase in trophic factors and activates the regeneration of nerve cells (Silverstone et al., 2012).
In addition, it has a high affinity for 5HT7 receptors, the association of which with symptoms of depression and circadian rhythm disorders has been proven experimentally. Antagonism of norkvetiapine in relation to these receptors contributes to the manifestation of the antidepressant effects of quetiapine (Sumegi et al., 2008). When comparing quetiapine and norkvetiapine with antidepressants in vitro, norkvetiapin showed the same activity against the norepinephrine transporter, as well as some antidepressants, while quetiapine was inactive.
In view of the foregoing, it can be concluded that quetiapine’s effectiveness for reducing depression symptoms is due, in part, to the pharmacological properties of its active metabolite, norkvetiapin, which selectively inhibits the reuptake of noradrenaline, acts as a partial agonist of 5-HT1A receptors, as well as antagonist of presinaptic? 2, 5-HT2C and 5-HT7 receptors (Bortnick et al., 2011).
Monopolar and bipolar depression
The clinical activity of quetiapine has a number of differences from other atypical antipsychotics, which is why this drug is quite effective in treating bipolar depression, MDD, and generalized anxiety disorder (GAD) (Suppes et al., 2008). For a long time, atypical antipsychotics have been banned for use in the treatment of BAR, as they were thought to provoke the symptoms of depression. However, recent studies have found that drugs such as quetiapine, aripiprazole, and lurazidone can be used in the treatment of both phases of BAR (Riedel et al., 2011). The affinity of these drugs for various 5HT receptors has a significant effect on their normo-chemical properties. By binding to these receptors, they, as well as lithium, alter the signal transduction along the intracellular pathways and the activity of nerve growth factor (Rush, 2010; Connolly et al., 2011).
Observing patients with ARD, clinicians determined that they most often had symptoms of depression rather than mania (Bakken et al., 2011). In this case, depression may be in the form of a major depressive episode requiring hospitalization, or chronic with subthreshold symptoms, as well as other symptoms, such as anxiety, somatic complaints, substance abuse, etc. Therefore, it is very important to choose the optimal treatment for the depressive phase of BAR. Data from several studies have shown that quetiapine monotherapy can be effective in this case. The recommended dosage regimen for quetiapine for depressive episodes: 1st day — 50 mg, 2nd — 100 mg, 3rd day — 200 mg, 4th and the next 300 mg. With BDR, quetiapine is recommended as an additional therapy according to the following scheme: 1st day – 50? Mg, 2nd – 100? Mg, 3rd and 4th – 150? Mg, the recommended daily dose is 150-300? Mg.