Chonnam Med J.  2017 Jan;53(1):1-13. 10.4068/cmj.2017.53.1.1.

Mixed States in Bipolar Disorder: Etiology, Pathogenesis and Treatment

• Muneer A

• KMID: 2367335
• DOI: http://doi.org/10.4068/cmj.2017.53.1.1

Abstract

Many bipolar disorder patients exhibit mixed affective states, which portend a generally more severe illness course and treatment resistance. In the previous renditions of Diagnostic and Statistical Manual mixed states were narrowly defined in the context of bipolar I disorder, but with the advent of DSM-5 the term "mixed episode" was dropped and replaced by "mixed features" specifier which could be broadly applied to manic, hypomanic and depressive episodes in both the bipolar spectrum and major depressive disorders. This paradigm shift reflected their significance in the prognosis and overall management of mood disorders, so that the clinicians should thoroughly familiarize themselves with the contemporary notions surrounding these conditions. The purpose of this manuscript is to bring to light the current conceptualizations regarding the etiology, pathogenesis and treatment of mixed states. To achieve this goal, in June 2016 an extensive literature search was undertaken using the PubMed database. Some exploratory terms utilized included "mixed states", "mixed episodes", "switching", "rapid cycling" cross referenced with "bipolar disorder". Focusing on the most relevant and up to date studies, it was revealed that mixed states result from genetic susceptibility in the circadian and dopamine neurotransmission apparatuses and disturbance in the intricate catecholamine-acetylcholine neurotransmission balance which leads to mood fluctuations. The management of mixed states is challenging with atypical antipsychotics, newer anticonvulsants and electroconvulsive therapy emerging as the foremost treatment options. In conclusion, while progress has been made in the neurobiological understanding of mixed states, the currently available therapeutic modalities have only shown limited effectiveness.

Keyword

Bipolar Disorder; Depressive Disorder, Major; Acetylcholine; Catecholamines; Dopamine

MeSH Terms

Acetylcholine
Anticonvulsants
Antipsychotic Agents
Bipolar Disorder*
Catecholamines
Depressive Disorder, Major
Dopamine
Electroconvulsive Therapy
Genetic Predisposition to Disease
Humans
Mood Disorders
Prognosis
Synaptic Transmission
Acetylcholine
Anticonvulsants
Antipsychotic Agents
Catecholamines
Dopamine

Figure

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  FIG. 1 Diagnostic criteria for manic, depressive and mixed states according to DSM-5. As opposed to previous editions, in DSM-5 the specifier “with mixed features” is used for manic, hypomanic or depressive episodes in bipolar spectrum and major depressive disorders. The term “mixed episode” used in the context of bipolar disorder type I has been discontinued in DSM-5. BD: bipolar disorder, MDD: major depressive disorder, MDE: major depressive episode.

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  FIG. 2 The burden of mixed symptoms in bipolar disorder. In bipolar disorder mixed states portend a pernicious course with increased suicidality and poor psychosocial functioning.

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  FIG. 3 Neurotransmitter basis of affective states in bipolar disorder. Data from different lines of evidence, but most importantly from the administration of pharmacological agents has elucidated the neurotransmitter abnormalities underlying different mood states in bipolar disorder. This hypothesis posits cathecholaminergic/cholinergic imbalance as central to the pathogenesis of mixed states. See text for further details.

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  FIG. 4 Unifying hypothesis of mood switching and mixed states in bipolar disorder. In bipolar disorder, circadian rhythm perturbations play a key role. To date, several polymorphisms in the circadian apparatus genes have been identified. Now a mechanistic link has been proposed which involves mesolimbic dopamine transmission. Mutations in Clock genes lead to a hyperdopaminergic state and precipitation of manic episodes. Polymorphisms in the dopamine transporter (DAT) gene further contribute to this disturbance. Mood switching is secondary to an imbalance in cholinergic neurotransmission, with decreased functioning of acetylcholinestrase and increased synaptic acetylcholine. This induces depressive symptoms, and gives rise to mixed states and rapid cycling. D/A: dopamine, TH: tyrosine hydroxylase, VTA: ventral tegmental area.

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  FIG. 5 The contemporary perspective of the treatment of mixed states in bipolar disorder. Mixed states are difficult to treat and no single agent is effective on its own, so that a combination of medications is often employed. Among the first line drugs are 2nd and 3rd generation antipsychotics, used alone or in conjunction with classical mood stabilizers. In this respect newer anticonvulsants show a favorable profile with good safety and efficacy parameters. Electroconvulsive therapy is an option in refractory cases.

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