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Neurobiological Bases of Quetiapine Antidepresant Effect in the Bipolar Disorder

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Neurobiological Bases of Quetiapine Antidepresant Effect in the Bipolar Disorder Originals E. Prieto 1 Neurobiological bases of quetiapine J. A. Micó 2 J. J. Meana 3 antidepresant effect in the S. Majadas 1 bipolar disorder 1 Neurosciences, Medical Department 3 Pharmacology Department AstraZeneca Farmacéutica (Spain) Medical School University of Basque Country. CIBERSAM 2 Neurosciences, Pharmacology and Psychiatry Department Unit. Medical School University of Cádiz. CIBERSAM Bipolar disorder is considered an important public va la más importante en términos de frecuencia, duración health problem in the world. The depressive phase is the y afectación de la calidad de vida. El tratamiento habitual most important in terms of frequency, duration, and impair- de la depresión bipolar suele incluir antidepresivos, euti- ment of the quality of life. Common treatment of bipolar mizantes y antipsicóticos en diversas combinaciones, sin depression usually includes antidepressants, mood stabili- que ninguno de ellos disponga de la indicación para ello. zers and antipsychotics in different combinations, despite La quetiapina se ha convertido en el primer fármaco en not having a specific indication for that. Quetiapine is the Europa en conseguir una indicación específica para el first drug in Europe that has obtained a specific indication tratamiento de la depresión bipolar, gracias a un perfil for the treatment of bipolar depression, due to a pharmaco- farmacológico que le permite actuar sobre los tres siste- logic profile that makes it to act on the three neurotrans- mas de neurotransmisores implicados en la neurobiología mitter systems involved in bipolar depression neurobiology. de la depresión bipolar. Sobre el sistema dopaminérgi- Regarding the dopaminergic pathway, quetiapine leads to an co la quetiapina induce un aumento de la liberación de increasing of prefrontal dopamine release by antagonism of dopamina prefrontal gracias principalmente a su acción antagonista 5-HT , agonista parcial 5-HT y antagonis- 5-HT 2A receptors, partial agonist of 5-HT 1A and antagonism 2A 1A of α2 adrenoceptors. Quetiapine also enhances the seroto- ta α2 adrenérgico. La quetiapina mejora también la neu- ninergic transmission by increasing the density of receptors rotransmisión serotoninérgica mediante el aumento de la densidad de receptores 5-HT en el córtex prefrontal y 5-HT 1A in the prefrontal cortex and by antagonism of 5-HT 2A 1A receptors and α2 adrenoceptors. On the other hand, nor- el antagonismo 5-HT 2A y α2 adrenérgico. Por su parte, quetiapine, the main active metabolite of quetiapine, acts el principal metabolito activo de la quetiapina, norque- tiapina, actúa como antagonista 5-HT y es un potente as a 5-HT 2C antagonist and is a potent inhibitor of norepine- 2C phrine transporter (NET). NET inhibition leads to an increase inhibidor del transportador de noradrenalina (NET). La of noerpinephrine in the synapse, and together with the in- inhibición del NET se traduce en un aumento de la nora- crease of prefrontal dopamine and serotonin, could explain drenalina sináptica que, unido al aumento de dopamina the antidepressive effect demonstrated by quetiapine in prefrontal y de serotonina explicaría el efecto antidepre- several clinical trials. Quetiapine’s action on glutamatergic sivo demostrado por la quetiapina en diferentes ensayos and GABAergic receptors represents an interesting object of clínicos. La acción de la quetiapina sobre los receptores research, together with a potential neuroprotective effect glutamatérgicos y GABAérgicos constituye un interesan- that have already been observed in animal models. te objeto de estudio, al igual que un posible efecto neu- roprotector que ya ha empezado a observarse en modelos Key words: Bipolar disorder. Bipolar depression. Quetiapine. Neurobiological basis. animales. Actas Esp Psiquiatr 2010;38(1):22-32 Palabras clave: Trastorno bipolar. Depresión bipolar. Quetiapina. Bases neurobiológicas. Bases neurobiológicas del efecto antidepresivo de quetiapina en el trastorno bipolar INTRODUCTION El trastorno bipolar constituye un importante proble- ma de salud pública en el mundo, siendo la fase depresi- Bipolar disorder is considered one of the ten major pu- Correspondence: blic health problems in the world1 and one of the conditions Esther Prieto AstraZeneca Farmacéutica Spain having the greatest disease burden. Its pharmacological Parque Norte. Edificio Roble treatment is complex. The treatment regimes used are often C/ Serrano Galvache, 56 28033 Madrid (Spain) modified according to the disease phase and, in the clinical E-mail: [email protected] practice, multiple therapy with three or more drugs is very 22 Act Esp Psiquiatr 2010;38(1):22-32 26 E. Prieto, et al Neurobiological bases of quetiapine antidepresant effect in the bipolar disorder frequently used. These, on the other hand, generally belong that compared lithium vs placebo and other drugs in the to different therapeutic groups and, consequently, have di- management of mood disorders in the long term. This meta- fferent action mechanisms. One of these therapeutic groups analysis concluded that the patients treated with lithium is antipsychotics, whose presence in the treatment of bipolar have a lower risk of death by suicide than patients who re- disorder is increasingly more common. ceived an alternative treatment, whether placebo or another treatment. 13 However, in the studies on bipolar depression, The depressive phase of bipolar disorder is the most im- lithium presents a long latency of this effect (6–8 weeks). portant in terms of frequency and duration. Different stu- This is an important limitation for its use. 14,15 On the other dies have shown that patients with bipolar disorder spend hand, the two studies performed with valproic acid in acute more time in the depression phase than in the manic phase, depression showed positive results. However, the sample size and that the depressive phases have a greater impact than was so small (N=25 and N=18, respectively) that great care any of the other phases of the disease, both on functioning must be used when interpreting the results. 16,17 In regards to and quality of life of the patient as on the risk of suicide. 2-5 lamotrigine, of the five studies carried out in the acute de- Judd et al. 3 found that the patients with type 1 bipolar di- pressive phase, only one was able to demonstrate significant sorder had depressive symptoms three times longer than differences compared to the placebo. In the remaining four, those with manic/hypomanic symptoms. In the case of type the results were not significant, 18 this being a reason why la- 2 bipolar disorder, this value increases, reaching the time motrigine has no therapeutic indication for the acute phase with depressive symptoms of 40 times that of those with of bipolar depression. hypomanic ones. 4 The clinical importance of these findings directly affects the therapeutic management. Furthermo- On the other hand, atypical antipsychotics have been re, a significant percentage of patients have subsyndromic used widely in the treatment of mania and practically all symptoms after remission of the acute episodes, fundamen- have a specific indication in this phase. The studies carried tally depressive type, which have been associated to worse out with olanzapine made it possible for this antipsychotic psychosocial functionality and greater risk of relapse. 6 to be approved for use in the prevention of recurrences of mania in patients who had previously responded to olanza- In spite of the enormous impact of the depressive symp- pine in the acute mania phase. However, studies that were toms on the course of the disease, until recently, there was conducted in bipolar depression showed some anti-depres- no drug available with a specific indication for the treatment sive efficacy, but they were based on the improvement of of bipolar depression. The drugs used most in the clinical symptoms that are not considered core in depression, such practice to treat this phase, as the antidepressants and some as inner tension, sleep disorders, and appetite disorders.19 mood stabilizing drugs, have some limitations, such as their Olanzapine does not have a specific indication for the slow action onset, side effects, absence of response in a part treatment of bipolar depression. 20 of the patients, etc. Recently, the Spanish Drug Agency has approved the Bipolar depression has been treated traditionally with use of quetiapine, both in its immediate release formulation antidepressants, known for their efficacy in the treatment and extended release one, for the treatment of depression of unipolar depression. 7,8 Standing out among them is the within type 1 and type 2 bipolar disorder, converting it into use of selective serotonin reuptake inhibitors (SSRI) and dual the first drug in Europe to obtain this approval. serotonin-norepinephrine reuptake inhibitors (SNRI). Howe- ver, the use of antidepressants in short and long term mono- The clinical trials conducted with immediate release and therapy in bipolar depression is debatable, due to the risk of extended release quetiapine in bipolar depression have de- induction of shift to mania or rapid cycling. 9,10 Although the monstrated that it has short and long-term antidepressant clinical data on the efficacy of its use in combined treatment activity, which is the basis for the previously mentioned in- with mood stabilizers are limited, in the clinical practi- dication. Furthermore, two already published clinical trials ce this drug combination is the one used the most in the in maintenance phase (clinical trials 126 and 127) 21,22 have treatment of bipolar depression in Spain, even though there shown that quetiapine is effective in the prevention of ma- is no clear evidence on its benefits. 11 Thus, in the STEP-BD nic and depressive recurrences in the long-term treatment, study, in which the use of antidepressants as adjuvant the- and independently of the index episode of the patient (ma- rapy to mood stabilizers versus placebo was compared, no nic, depressive or mixed), thus demonstrating its potential differences were found in terms of duration of the recovery, long-term capacity for mood stabilization.
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