Dopamine sudden depletion as a model for mixed depression

Abstract

Up to date research on Bipolar Disorders’ phenomenology is in keeping with early descriptions made by E. Kraëpelin regarding the overlap in clinical presentation of both manic and depressive symptoms, namely, mixed states. The latter constitute a highly prevalent and characteristic clinical presentation of Bipolar Disorders’ and entail therapeutic difficulties, prognostic implications and increased suicidal risk. Notwithstanding, mixed states’, more specifically mixed depression, have been underestimated and bypassed to the point where currently neither diagnostic criteria nor specific therapeutic recommendations are provided. In addition to the lack of agreement on nosography and diagnostic criteria, mixed depression is usually excluded from Bipolar Disorders’ neurobiological models. Furthermore, renewed interest in the role of dopamine in Bipolar Disorders’ physiopathology has left aside hypothesis that may account for the aforementioned clinical presentation. Interestingly enough, other syndromes arising from sudden dopamine depletion such as neuroleptic dysphoria or withdrawal syndromes from dopaminergic drugs, bear remarkable clinical similarities with mixed depression. These syndromes have been subject of further research and may thus provide a model for mixed states’ physiopathology.

Indeed, this article accounts for clinical similarities between mixed depression, neuroleptic induced dysphoria, and other behavioural syndromes arising from sudden dopamine depletion. After reviewing neurochemical basis of such syndromes we present, to the best of our knowledge, the first neurobiological hypothesis for mixed depression. Specifically, such hypothesis regards over activation symptoms as auto regulatory attempts to compensate for sudden dopaminergic depletion. This hypothesis provides with a beginning step for the neglected problem of mixed depression, a non-antithetic link between the dopaminergic hypothesis for both manic and depressive symptoms, a plausible explanation regarding inter individual variability to mixed depression susceptibility, and suggests new approaches for the development of novel treatments in which dopamine dysregulation should be targeted.

Introduction

Mixed states (MS) were first conceptualized by W. Weygandt in the late 1890s [1] but it was not until the sixth edition of Kraëpelin textbook [2] that they deserved more attention and were included in a separated section. The description of MS was in keeping with both Kraëpelin and Weygandt’s view of mood disorders [3], highlighting the unity of manic depressive insanity (illness). If symptoms of opposite polarity were present during the same episode, then mania/hypomania and depression could not be distinct disorders [4], [5].

The pioneer vision of pre pharmacology psychiatrists has been further validated by recent clinical studies with modern statistics which depict a clinical picture where approximately one third of acute episodes have mixed symptomatology and where boundaries between depression and mania are a quantitative transition rather than a categorical cut off [6], [7]. Benazzi, has gone further in clinically and epidemiologically characterizing the concept of MS, particularly mixed depression (MxD) [5]. Currently, the problem of MS in general has been progressively marginalized and bypassed. The DSM IV-TR lacks proper clinical, therapeutic, or pathophysiologyical definition and there is neither unified diagnostic criteria for MS in general nor for MxD in particular to the extend that the International Society of Bipolar Disorders’ (ISBD) Task Force excluded them from its diagnostic guidelines [8]. In the same fashion, specific criteria for MS were not included in the ISBD recent publication on nomenclature, course and outcome of bipolar disorders [9]. Despite reported prevalence of up to 39%, increased suicidal risk and specific therapeutic and prognostic implications [10], most treatment guidelines for BD fail to provide recommendations for MS and research about their treatment is marginal [11]. Finally, according to the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders draft, MS would be replaced and relegated to a course specifier.

Accordingly, pathophysiological models proposed for BD have avoided the problem of MxD. Although many intend to account for mania, depression and mood dysregulation, only a few psychological models have attempted to address MxD [12] and none at the level of neurotransmission or neurobiology. While nomenclature and diagnostic discussions allow for pragmatic solutions, any valid pathophysiological model pretending to depict BD phenomenology should not ignore that most episodes do not present themselves as pure mania or depression but rather, more than half of the time, as episodes with joint symptomatology.

Despite the fact that renewed consideration on the role of dopamine (DA) in the psychopathology of BD has resulted in new plausible models for this condition, the tendency of bypassing MxD remains [12]. Interestingly enough, neuroleptic-induced dysphoria (ND) and other syndromes secondary to sudden DA depletion, bear clear symptomatic overlap with MxD and may thus provide a novel approach in understanding its pathophysiology. The present article reviews DA depletion clinical presentation while discussing its similarities with MxD, presents current evidence of dopaminergic depletion models in its pathophysiology, and poses a dopaminergic model for MxD.