Reversal of Dopamine Supersensitivity as a Mechanism of Action of Clozapine

Kim, David D.; Barr, Alasdair M.; Honer, William G.; Procyshyn, Ric M.

doi:10.1159/000491700

Cited by 12 publications

(8 citation statements)

References 11 publications

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“…Similar mechanisms, subsumed under the concept of supersensitivity psychosis, may apply to the use of antipsychotics in schizophrenia and mood disorders. 78,79 The oppositional model of tolerance is also consistent with the use of psychotropic medications as recreational drugs. 80 If we take into consideration the potential benefits, the likelihood of responsiveness, and the potential adverse events and vulnerabilities entailed by oppositional mechanisms, we would be inclined to target the application of AD only to the most severe and persistent cases of depression for the shortest possible time, and avoid their utilization in anxiety disorders (unless a major depressive disorder is present or other treatments have been ineffective).…”

Section: Resultsmentioning

confidence: 67%

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May antidepressant drugs worsen the conditions they are supposed to treat? The clinical foundations of the oppositional model of tolerance

Fava

2020

Therapeutic Advances in Psychopharmacology

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In recent years there has been a considerable debate on antidepressant drugs. Continued drug treatment with antidepressant medications may stimulate processes that run counter to the initial acute effects of a drug. The oppositional model of tolerance may explain loss of treatment efficacy during maintenance treatment and the fact that some side effects tend to occur only after a certain time. These processes may also direct the illness into a treatment-unresponsive course, including manifestations of bipolar disorder or paradoxical reactions. When drug treatment ends, oppositional processes no longer encounter resistance, resulting in potential onset of new withdrawal symptoms, persistent post-withdrawal disorders, hypomania, and resistance to treatment if it is reinstituted. In all these cases, antidepressant medications may constitute a form of iatrogenic comorbidity, which increases chronicity and vulnerability to depressive episodes. Antidepressant medications are essential drugs for the treatment of major depressive episodes. They are less likely, however, to provide protection for relapse prevention. Current prescription practices need to be reformulated in light of consideration of vulnerabilities and adverse effects of treatment. The oppositional model of tolerance provides a conceptual framework for weighing all these elements in the individual case. The model does not appear to apply to all patients who undergo treatment with AD, but only to a part of them. Studying the variables that are associated with such occurrence in certain patients and not in others would be one of the most important tasks of current therapeutic research. Current diagnostic systems in psychiatry do not consider the iatrogenic components of psychopathology, and can be applied to only patients who are drug free. They are suited for a patient who no longer exists: most of the cases that are seen in psychiatric clinical practice receive psychotropic drugs and such treatment is likely to affect prognosis and treatment choices.

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Section: Resultsmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 68%

May antidepressant drugs worsen the conditions they are supposed to treat? The clinical foundations of the oppositional model of tolerance

Fava

2020

Therapeutic Advances in Psychopharmacology

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“…The SGA clozapine is the preferred drug for treatment resistant psychosis (11)(12)(13)(14)(15), producing therapeutic responses in approximately 30% of patients previously refractory to other antipsychotics (16)(17)(18), possibly reflecting a unique mechanism of action based on its complex pharmacology (19).…”

Section: Introductionmentioning

confidence: 99%

A Focused Review of the Metabolic Side-Effects of Clozapine

et al. 2021

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The second generation antipsychotic drug clozapine represents the most effective pharmacotherapy for treatment-resistant psychosis. It is also associated with low rates of extrapyramidal symptoms and hyperprolactinemia compared to other antipsychotic drugs. However, clozapine tends to be underutilized in clinical practice due to a number of disabling and serious side-effects. These are characterized by a constellation of metabolic side-effects which include dysregulation of glucose, insulin, plasma lipids and body fat. Many patients treated with clozapine go on to develop metabolic syndrome at a higher rate than the general population, which predisposes them for Type 2 diabetes mellitus and cardiovascular disease. Treatments for the metabolic side-effects of clozapine vary in their efficacy. There is also a lack of knowledge about the underlying physiology of how clozapine exerts its metabolic effects in humans. In the current review, we focus on key studies which describe how clozapine affects each of the main symptoms of the metabolic syndrome, and cover some of the treatment options. The clinical data are then discussed in the context of preclinical studies that have been conducted to identify the key biological substrates involved, in order to provide a better integrated overview. Suggestions are provided about key areas for future research to better understand how clozapine causes metabolic dysregulation.

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“…These direct neurotransmitter-associated effects cannot sufficiently explain the remarkable efficacy of clozapine in treatment-refractory SZ. This implies that other non-neurotransmitter-associated effects may be expected to underlie its outstanding antipsychotic properties [9][10][11][12]. Moreover, both clozapine and its two major metabolites, clozapine-N-oxide (CNO) and N-desmethylclozapine (NDC), exhibit neuroprotective and anti-inflammatory properties [13,14].…”

Section: Introductionmentioning

confidence: 99%

Clozapine modulates retinoid homeostasis in human brain and normalizes serum retinoic acid deficit in patients with schizophrenia

et al. 2020

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The atypical antipsychotic clozapine is one of the most potent drugs of its class, yet its precise mechanisms of action remain insufficiently understood. Recent evidence points toward the involvement of endogenous retinoic acid (RA) signaling in the pathophysiology of schizophrenia. Here we investigated whether clozapine may modulate RA-signaling. Effects of clozapine on the catabolism of all-trans RA (at-RA), the biologically most active metabolite of Vitamin A, were assessed in murine and human brain tissue and peripheral blood-derived mononuclear cells (PBMC). In patients with schizophrenia with and without clozapine treatment and matched healthy controls, at-RA serum levels and blood mRNA expression of retinoidrelated genes in PBMCs were quantified. Clozapine and its metabolites potently inhibited RA catabolism at clinically relevant concentrations. In PBMC-derived microsomes, we found a large interindividual variability of the sensitivity toward the effects of clozapine. Furthermore, at-RA and retinol serum levels were significantly lower in patients with schizophrenia compared with matched healthy controls. Patients treated with clozapine exhibited significantly higher at-RA serum levels compared with patients treated with other antipsychotics, while retinol levels did not differ between treatment groups. Similarly, in patients without clozapine treatment, mRNA expression of RA-inducible targets CYP26A and STRA6, as well as at-RA/retinol ratio, were significantly reduced. In contrast, clozapine-treated patients did not differ from healthy controls in this regard. Our findings provide the first evidence for altered peripheral retinoid homeostasis in schizophrenia and suggest modulation of RA catabolism as a novel mechanism of action of clozapine, which may be useful in future antipsychotic drug development.

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Reversal of Dopamine Supersensitivity as a Mechanism of Action of Clozapine

Cited by 12 publications

References 11 publications

May antidepressant drugs worsen the conditions they are supposed to treat? The clinical foundations of the oppositional model of tolerance

May antidepressant drugs worsen the conditions they are supposed to treat? The clinical foundations of the oppositional model of tolerance

A Focused Review of the Metabolic Side-Effects of Clozapine

Clozapine modulates retinoid homeostasis in human brain and normalizes serum retinoic acid deficit in patients with schizophrenia

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