Atypical antipsychotics in bipolar depression: Potential mechanisms of action

Department of Psychiatry, The University of British Columbia, UBC Hospital, Vancouver, Canada.
The Journal of Clinical Psychiatry (Impact Factor: 5.5). 02/2005; 66 Suppl 5(Suppl 5):40-8.
Source: PubMed


"Conventional" antidepressants, such as the selective serotonin reuptake inhibitors (SSRIs), bupropion, or serotonin-norepinephrine reuptake inhibitors, are not recommended as monotherapy for bipolar depression. Although they are likely to provide effective symptom relief in combination with mood stabilizers, the risk of precipitating a switch to mania often complicates their use even as combination therapy. Recently, 2 psychotropic medications approved for treating acute mania, olanzapine and quetiapine, have also been shown to possess antidepressant activity without destabilizing mood and, as such, are potential mood stabilizers. This article aims to review the mechanism of action of conventional antidepressants and newer agents that are effective in the treatment of bipolar depression. A number of mechanisms have been postulated to play a role in the effective treatment of bipolar depression, including targets as diverse as serotonin (5-HT), norepinephrine, dopamine, gamma-aminobutyric acid (GABA), glutamate, and various second messenger signaling pathways. A review of the data reveals an important point of commonality among the antidepressant treatments, olanzapine, and quetiapine. Antidepressant treatments, such as norepinephrine reuptake inhibitors, SSRIs, and electroconvulsive therapy, induce a reduction of 5-HT(2A) receptors. Both olanzapine and quetiapine not only are antagonists at this receptor but also induce downregulation of 5-HT(2A) receptors. It is possible that the antidepressant efficacy of these agents is mediated by this receptor, while the additional benefit of olanzapine and quetiapine over unimodal antidepressant treatments, in terms of stabilizing mood, may be provided by their concomitant dopamine D(2) antagonism. Further studies should be conducted to examine these hypotheses.

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    • "Norquetiapine (N-desalkyl quetiapine) is an active metabolite of quetiapine with high affinity for norepinephrine transporters and partial agonism at serotonin 5-HT1A receptors.8 The mechanism by which quetiapine ameliorates depression may include 5-HT2A antagonism, 5-HT1A receptor partial agonism, α2b receptor antagonism, and D2 receptor antagonism.9 While the common side effects of quetiapine are somnolence, postural hypotension, dizziness, and dry mouth, some serious side effects include elevated blood glucose levels, diabetic coma, and ketoacidosis.5 "
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    • "Psychosocial impairments also significantly increase with each increment in the severity of the symptoms of depression (Judd et al., 2005). Although the pharmacological guidelines for treatment for bipolar disorder are well-established (American Psychiatric Association, 2002; Kowatch et al., 2005; Yatham et al., 2005), the treatment in practice remains less than ideal. Most patients still have breakthrough episodes or significant residual symptoms while on medication, and functional deficits often remain even when patients are in remission (Bauer et al., 2002). "
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    • "In patients treated with quetiapine fumarate, plasma concentrations of norquetiapine are only slightly lower than those of the parent molecule (DeVane and Nemeroff, 2001; Winter et al., 2008; Nikisch et al., 2010; Nord et al., 2011). Quetiapine has been extensively characterized and shows affinity at multiple neurotransmitter receptors in the brain, including serotonin 5-HT 1A , 5-HT 2A and 5-HT 2C , dopamine D 1 and D 2 , histamine H 1 and adrenergic α1 and α2 receptors (Goldstein, 1999; Nemeroff et al., 2002; Yatham et al., 2005). "
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    ABSTRACT: Quetiapine, originally developed as an antipsychotic, demonstrates efficacy in clinical studies of schizophrenia, bipolar mania and depression, major depressive disorder and generalized anxiety disorder. This broad spectrum of efficacy was not predicted from the preclinical pharmacology of quetiapine. Binding studies in vitro show that quetiapine and its major active human metabolite, norquetiapine, have moderate to high affinity for dopamine D2 and serotonin 5-HT2A receptors, while norquetiapine alone has high affinity for the norepinephrine transporter (NET). This positron emission tomography (PET) study measured NET occupancy in human subjects treated with extended-release quetiapine (quetiapine XR) at doses relevant in the treatment of depression. PET measurements using the specific NET radioligand (S,S)-[18F]FMeNER-D2 were performed before and after quetiapine XR treatment at 150 and 300 mg/d for 6-8 d in nine healthy males (aged 21-33 yr). Regions of interest were defined for the thalamus, using the caudate as reference region. NET occupancy was calculated using a target:reference region ratio method. Plasma concentrations of quetiapine and norquetiapine were monitored during PET measurements. Following quetiapine XR treatment, the mean NET occupancy in the thalamus was 19 and 35%, respectively, at quetiapine XR doses of 150 and 300 mg/d. The estimated plasma concentration of norquetiapine corresponding to 50% NET occupancy was 161 ng/ml. This is the first demonstration of NET occupancy by an antipsychotic in the human brain. NET inhibition is accepted as a mechanism of antidepressant activity. NET occupancy may therefore contribute to the broad spectrum of efficacy of quetiapine.
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