Antidepressant-induced Dopamine Receptor Dysregulation: A Valid Animal Model of Manic-Depressive Illness

Abstract

Background: Mania seems to be associated with an increased dopamine (DA) transmission. Antidepressant treatments can induce mania in humans and potentiated DA transmission in animals, by sensitizing DA D2 receptors in the mesolimbic system. We have suggested that the sensitization of D2 receptors may be responsible of antidepressant-induced mania. This review aims to report the experimental evidence that led to the hypothesis that antidepressant-induced DA receptors dysregulation can be considered an animal model of bipolar disorder.Methods: We reviewed papers reporting preclinical and clinical studies on the role of DA in the mechanism of action of antidepressant treatments and in the patho-physiology of mood disorders.Results: A number of preclinical and clinical evidence suggests that mania could be associated with an increased DA activity, while a reduced function of this neurotransmission might underlie depression. Chronic treatment with imipramine induces a sensitization of DA D2 receptors in the mesolimbic system, followed, after drug discontinuation, by a reduced sensitivity associated with an increased immobility time in forced swimming test of depression (FST). Blockade of glutamate NMDA receptors by memantine administration prevents the imipramine effect on DA receptors sensitivity and on the FST.Conclusion: We suggest that chronic treatment with antidepressants induces a behavioural syndrome that mimics mania (the sensitization of DA receptors), followed by depression (desensitization of DA receptors and increased immobility time in the FST), i.e. an animal model of bipolar disorder. Moreover the observation that memantine prevents the “bipolar-like” behavior, suggests that the drug may have an antimanic and mood stabilizing effect. Preliminary clinical observations support this hypothesis.

Agitated depression in bipolar disorder

“…At the same time, the correlation of specific lifetime clinical features with AD suggests, in agreement with previous empirical evidence, that particular care is needed in the pharmacological treatment of bipolar depression symptomatology 30,40,41. Our finding within a large sample highlights the need for the detection of agitated features in both past and current episodes of depression among individuals with bipolar disorder which could enable clinicians to identify those at elevated risk of future suicide attempts.Our data have clinical relevance for the diagnosis and treatment of AD in bipolar disorder.…”

“…At the same time, the correlation of specific lifetime clinical features with AD suggests, in agreement with previous empirical evidence, that particular care is needed in the pharmacological treatment of bipolar depression symptomatology. 30,40,41 For example, depressive episodes with panic comorbidity are often treated with antidepressants, 42 however, the treatment should be closely monitored in order to identify possible psychomotor agitation since such symptomatology can worsen with antidepressants 8,16 and, at worst, increase risk of suicide. 30,35 Moreover, individuals who experience both AD and dysphoric mania during their lifetime could belong to a subtype of bipolar disorder characterized by mixed episodes with a high risk of suicide attempt for which antidepressant medication is not recommended.…”

Doxycycline reversal of amphetamine-induced mania-like behavior is related to adjusting brain monoamine abnormalities and antioxidant effects in primary hippocampal neurons

“…The forced swim test was applied to model an increase in energetic-behavioral components (behavioral vigor) and goal-directed behavior (Demontis et al, 2016), which are important symptoms of bipolar mania. In our results (Fig.…”

Antidepressant emergent mood switch in major depressive disorder: onset, clinical correlates and impact on suicidality

“…However, if, over time, D2/3 receptor levels reduce but dopamine transporter levels do not normalise, this would then lead to reduced dopaminergic transmission, leading to depression and, in turn, a compensatory upregulation of D2/3 receptor levels, precipitating a further phase switch ( Ashok et al ., 2017 ). AD drugs could interfere with this cycle not only by blockading monoamine transporters but also because they might induce changes in dopamine receptor sensitivity ( Demontis et al ., 2017 ). In bipolar spectrum depression AEMS could be generated by a similar mechanism, however patients who express more bipolar markers would need a shorter time exposure to AD treatment before switching to a state of mood activation.…”