Athanasios Koukopoulos

The International Society for Bipolar Disorders (ISBD) Task Force Report on Antidepressant Use in Bipolar Disorders

OBJECTIVE The risk-benefit profile of antidepressant medications in bipolar disorder is controversial. When conclusive evidence is lacking, expert consensus can guide treatment decisions. The International Society for Bipolar Disorders (ISBD) convened a task force to seek consensus recommendations on the use of antidepressants in bipolar disorders. METHOD An expert task force iteratively developed consensus through serial consensus-based revisions using the Delphi method. Initial survey items were based on systematic review of the literature. Subsequent surveys included new or reworded items and items that needed to be rerated. This process resulted in the final ISBD Task Force clinical recommendations on antidepressant use in bipolar disorder. RESULTS There is striking incongruity between the wide use of and the weak evidence base for the efficacy and safety of antidepressant drugs in bipolar disorder. Few well-designed, long-term trials of prophylactic benefits have been conducted, and there is insufficient evidence for treatment benefits with antidepressants combined with mood stabilizers. A major concern is the risk for mood switch to hypomania, mania, and mixed states. Integrating the evidence and the experience of the task force members, a consensus was reached on 12 statements on the use of antidepressants in bipolar disorder. CONCLUSIONS Because of limited data, the task force could not make broad statements endorsing antidepressant use but acknowledged that individual bipolar patients may benefit from antidepressants. Regarding safety, serotonin reuptake inhibitors and bupropion may have lower rates of manic switch than tricyclic and tetracyclic antidepressants and norepinephrine-serotonin reuptake inhibitors. The frequency and severity of antidepressant-associated mood elevations appear to be greater in bipolar I than bipolar II disorder. Hence, in bipolar I patients antidepressants should be prescribed only as an adjunct to mood-stabilizing medications.

Issues for DSM-5: Whither Melancholia? The Case for Its Classification as a Distinct Mood Disorder

Melancholia, a syndrome with a long history and distinctly specific psychopathological features, is inadequately differentiated from major depression by the DSM-IV specifier. It is neglected in clinical assessment (e.g., in STAR*D [1]) and treatment selection (e.g., in the Texas Medication Algorithm Project [2]). Nevertheless, it possesses a distinctive biological homogeneity in clinical experience and laboratory test markers, and it is differentially responsive to specific treatment interventions. It therefore deserves recognition as a separate identifiable mood disorder. Melancholia has been variously described as “endogenous,” “endogenomorphic,” “autonomous,” “type A,” “psychotic,” and “typical” depression (3–6). In contrast to the current DSM criteria for the melancholia specifier (features of which are often shared with major depression), it has characteristic clinical features (5–7).

DSM-5 criteria for depression with mixed features: a farewell to mixed depression

To review the DSM‐5 proposed criteria for mixed depression in light of robust and consistent historical and scientific evidence.

Melancholia agitata and mixed depression

Objective:  The diagnostic entity of major depressive episode includes both simple and agitated or mixed depression. Mixed depression is characterized by a full depressive episode with several symptoms of excitatory nature. Mixed depressions worsen if treated with antidepressants.

Ewald Hecker’s description of cyclothymia as a cyclical mood disorder: its relevance to the modern concept of bipolar II

1 . Historical note basis until they could be back on their feet. His work with outpatients and his intimate acquaintance with Ewald Hecker (1843–1909) was a disciple of Karl them enabled him to make observations which Ludwig Kahlbaum and his closest assistant for many escaped hospital psychiatrists. His incisive clinical years at the Kahlbaum Sanitarium in Goerlitz, Silesia description and his sophisticated understanding of (Germany). His cousin was Kahlbaum’s first wife. psychopathology made Hecker (1898) not only a Their collaboration was extremely fruitful and proforerunner, but also one who anticipated today’s duced landmark works on hebephrenia and conceptions of cyclothymia as the basis of bipolar II cyclothymia. Hecker’s progressive approach to psydisorder (Dunner et al., 1976; Akiskal et al., 1977; chiatry, which he recommended to Kahlbaum, comAkiskal et al., 1979; Akiskal, 1981; Depue et al., bated the coercive methods of his time and placed 1981; Cassano et al., 1992; American Psychiatric the accent on public education to eliminate the Association, 1994; Brieger and Marneros, 1997; stigma attached to mental illness. Like Kahlbaum, he Hantouche et al., 1998; Akiskal et al., 2000; Akiskal never attained a university chair in psychiatry, and Pinto, 1999). Indeed, he described cyclothymia perhaps because of his liberal ideas. Instead, he as brief depressions with mild excitements of short worked at his own private hospital in Wiesbaden, duration (measured in days), as well as longer which he bought in 1891. Hecker attained a reputadepressions (lasting weeks to months) and followed tion as hypnotherapist and psychotherapist for paby brief hypomanias. The latter of course correspond tients with cyclothymia, anxiety and sleep disorders, to today’s concept of bipolar II. He proceeded to anticipating today’s outpatient combination of psyprovide a superb description of the clinical picture of chiatry and psychotherapy. He attached such imporbipolar II as we know it today. Even his recomtance to humane practices that he even accommomendations not to tamper too much with the depresdated some patients into his home on a temporary sive phase and instead endeavour to limit the hypomanic phase, resonates with contemporary advice (Akiskal and Pinto, 1999; Wehr and Goodwin, 1987; *Tel.: 1 39-06-687-4415; fax: 1 39-06-6880-2345. Akiskal and Mallya, 1987; Koukopoulos et al., 1990; E-mail address: a.koukopoulos@flashnet.it (A. Koukopoulos). Akiskal, 2001)—alas not heeded often enough! The

Mixed depressive states: Nosologic and therapeutic issues

This paper focuses on the clinical importance of affective mixed states with special attention given to agitated depression, which has lost its status as a mixed state in the DSM and ICD systems. Following a historical review of the topic, the psychopathological elements are examined. Psychic and motor agitation are considered equally important for the definition of agitated depression and the concept of latent agitated depression is introduced for those major depressive episodes that become agitated following antidepressant treatment. The thesis is advanced that the erroneous nosologic position of agitated depression and its treatment as simple, unipolar depression is at least partly responsible for the problematic issues of the unfavourable treatment outcome and high suicide rates among depressive patients. Sometimes it is more ‘inward anxiety and trembling’, a painful tension … sometimes it is an anxious restlessness, which finds an outlet in the most varied gestures, in states of violent excitement, and in heedless attempts at suicide. These moods are most frequently found in the periods of transition between states of depression and mania; they are, therefore, probably most correctly regarded as mixed states of depression and manic excitability. Emil Kraepelin, 1913 The inner unrest is the constant thing, the motor unrest is variable. Sir Aubrey Lewis, 1934

Suicide in a large population of former psychiatric inpatients

Aims:  The aim of this study was to identify predictors of completed suicide in a wide sample of psychiatric inpatients receiving retrospective and prospective DSM‐IV diagnoses.

Precursors of bipolar disorders: a systematic literature review of prospective studies.

OBJECTIVE To evaluate the presence of affective signs and symptoms as precursors of bipolar disorder in prospective studies, including assessment of their prevalence, duration, and predictive value. DATA SOURCES We followed PRISMA guidelines to search PubMed, CINAHL, PsycINFO, EMBASE, SCOPUS, and ISI Web of Science databases to May 31, 2013, using the terms bipolar disorder AND (antecedent* OR predict* OR prodrom* OR prospect*) AND (diagnosis OR development). Hand searching of identified reports led to additional relevant references. STUDY SELECTION We included only English-language articles containing (1) prospective, longitudinal studies with at least 2 structured clinical assessments (intake and follow-up); (2) no previous DSM-III or DSM-IV diagnoses of bipolar I or bipolar II; and (3) diagnostic outcome of bipolar I or bipolar II. Studies of subjects at familial risk of bipolar disorder were excluded, as these have been reviewed elsewhere. DATA EXTRACTION We tabulated details of study design, outcomes, precursors, and predictive value. Only studies reporting a positive predictive association were included. RESULTS In 26 published reports meeting selection criteria, methods varied widely in terms of design, duration of follow-up, ages, and populations investigated. Despite such heterogeneity in methods, findings were notably consistent. Precursors of bipolar disorder include mood lability, subsyndromal and major depression, subsyndromal hypomanic symptoms with or without major depression, cyclothymia and bipolar not otherwise specified, major depression with psychotic features, and other psychotic disorders. Bipolar disorder was also predicted by juvenile onset of major depression as well as frequency and loading of hypomanic or depressive symptoms. CONCLUSIONS Despite the limitations of published reports, prospectively identified precursors of bipolar disorder typically arose years prior to syndromal onset, often with significant early morbidity and disability. Prospectively identified precursors of bipolar disorder are generally consistent with findings in retrospective and family-risk studies. Combining precursors and other risk factors may increase predictive value, support earlier diagnosis, improve treatment, and limit disability in bipolar disorder.

The primacy of mania: a reconsideration of mood disorders.

In contemporary psychiatry, depression and mania are conceived as different entities. They may occur together, as in bipolar disorder, or they may occur separately, as in unipolar depression. This view is partly based on a narrow definition of mania and a rather broad definition of depression. Generally, depression is seen as more prominent, common, and problematic; while mania appears uncommon and treatment-responsive. We suggest a reversal: mania viewed broadly, not as simply episodic euphoria plus hyperactivity, but a wide range of excitatory behaviors; and depression seen more narrowly. Further, using pharmacological and clinical evidence, and in contrast to previous theories of mania interpreted as a flight from depression, we propose the primacy of mania hypothesis (PM): depression is a consequence of the excitatory processes of mania. If correct, current treatment of depressive illness needs revision. Rather than directly lifting mood with antidepressants, the aim would be to suppress manic-like excitation, with depression being secondarily prevented. Potential objections to, and empirical tests of, the PM hypothesis are discussed.

Antimanic and mood‐stabilizing effect of memantine as an augmenting agent in treatment‐resistant bipolar disorder

Memantine is a selective, uncompetitive N-methyl- D-aspartate (NMDA) receptor antagonist, currently used in the treatment of Alzheimers disease. Many clinical trials have demonstrated its tolerability and safety. We have suggested that antidepressants induce mania and rapid cycling by sensitizing dopamine D2 receptors and demonstrated that the sensitization induced by antidepressants requires the stimulation of NMDA receptors. It is tempting to suggest that the phenomenon of sensitization could underlie the spontaneous development and the course of mania as well.