Gabriele Sani

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.

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

The role of memantine in the treatment of psychiatric disorders other than the dementias: A review of current preclinical and clinical evidence

Memantine, a non-competitive NMDA receptor antagonist approved for Alzheimer’s disease with a good safety profile, is increasingly being studied in a variety of non-dementia psychiatric disorders. We aimed to critically review relevant literature on the use of the drug in such disorders. We performed a PubMed search of the effects of memantine in animal models of psychiatric disorders and its effects in human studies of specific psychiatric disorders. The bulk of the data relates to the effects of memantine in major depressive disorder and schizophrenia, although more recent studies have provided data on the use of the drug in bipolar disorder as an add-on. Despite interesting preclinical data, results in major depression are not encouraging. Animal studies investigating the possible usefulness of memantine in schizophrenia are controversial; however, interesting findings were obtained in open studies of schizophrenia, but negative placebo-controlled, double-blind studies cast doubt on their validity. The effects of memantine in anxiety disorders have been poorly investigated, but data indicate that the use of the drug in obsessive-compulsive disorder and post-traumatic stress disorder holds promise, while findings relating to generalized anxiety disorder are rather disappointing. Results in eating disorders, catatonia, impulse control disorders (pathological gambling), substance and alcohol abuse/dependence, and attention-deficit hyperactivity disorder are inconclusive. In most psychiatric non-Alzheimer’s disease conditions, the clinical data fail to support the usefulness of memantine as monotherapy or add-on treatment However, recent preclinical and clinical findings suggest that add-on memantine may show antimanic and mood-stabilizing effects in treatment-resistant bipolar disorder.

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.

Predominant polarity and temperament in bipolar and unipolar affective disorders

INTRODUCTION Recently, the concept of predominant polarity (two-thirds of episodes belonging to a single pole of the illness) has been introduced to further characterise subtypes of bipolar disorders. This concept has been proven to have diagnostic and therapeutic implications, but little is known on the underlying psychopathology and temperaments. With this study, we aimed to further validate the concept and explore its relationships with temperament. METHODS This study enrolled 143 patients with bipolar or unipolar disorder. We analysed predominant polarity in the sample of bipolar I patients (N=124), focussing on those who showed a clear predominance for one or the other polarity, and distinguishing manic/hypomanic (MP) from depressive polarity (DP), and a unipolar major depression (UP) group (N=19),. We also assessed temperament by means of the Temperament Evaluation of the Memphis, Pisa, Paris, and San Diego Autoquestionnaire (TEMPS-A). RESULTS Over 55% of the bipolar I sample fulfilled predominant polarity criteria, with two-thirds of those meeting criteria for MP and one third for DP. MP and DP were similar in scoring higher than UP on the hyperthymic/cyclothymic scales of the TEMPS-A; the UP group scored higher on the anxious/depressive scales. DISCUSSION Our results show that both bipolar I MP and DP subgroups are temperamentally similar and different from UP. Depression in DP bipolar I patients should be viewed as the overlap of depression on a hyperthymic/cyclothymic temperament. These findings confirm the value of the predominant polarity concept as well as the importance of temperaments to separate bipolar from unipolar disorders.

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.

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.

Mixed Depression: Clinical Features and Predictors of Its Onset Associated with Antidepressant Use

Background: Mixed depression (MxD) is narrowly defined in the DSM-IV and somewhat broader in the DSM-5, although both exclude psychomotor agitation as a diagnostic criterion. This article proposes a clinical description for defining MxD, which emphasizes psychomotor excitation. Methods: Two hundred and nineteen consecutive outpatients were diagnosed with an MxD episode using criteria proposed by Koukopoulos et al. [Acta Psychiatr Scand 2007;115(suppl 433):50-57]; we here report their clinical features and antidepressant-related effects. Results: The most frequent MxD symptoms were: psychic agitation or inner tension (97%), absence of retardation (82%), dramatic description of suffering or weeping spells (53%), talkativeness (49%), and racing or crowded thoughts (48%). MxD was associated with antidepressants in 50.7% of patients, with similar frequency for tricyclic antidepressants (45%) versus selective serotonin reuptake inhibitors (38.5%). Positive predictors of antidepressant-associated MxD were bipolar disorder type II diagnosis, higher index depression severity, and higher age at index episode. Antipsychotic or no treatment was protective against antidepressant-associated MxD. Conclusions: MxD, defined as depression with excitatory symptoms, can be clinically identified, is common, occurs in both unipolar depression and bipolar disorder, and is frequently associated with antidepressant use. If replicated, this view of MxD could be considered a valid alternative to the DSM-5 criteria for depression with mixed features.

Clinical risk factors for bipolar disorders: A systematic review of prospective studies

BACKGROUND Early phases and suspected precursor states of bipolar disorder are not well characterized. We evaluate the prevalence, duration, clinical features and predictive value of non-affective psychopathology as clinical risk factors for bipolar disorder in prospective studies. METHODS We screened PubMed, CINAHL, PsycINFO, Embase, SCOPUS, and ISI-Web of Science databases from inception up to January 31, 2014, following PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) and searched: bipolar disorder AND [antecedent⁎ OR predict⁎ OR prodrom⁎ OR prospect⁎ OR risk⁎] AND [diagnosis OR development]. We included only English language reports on prospective, longitudinal studies with two structured clinical assessments (intake and follow-up); no DSM intake diagnosis of bipolar-I or -II; diagnostic outcome was bipolar-I or -II. Details of study design, risk factors, and predictive value were tabulated. RESULTS We found 16 published reports meeting selection criteria, with varying study design. Despite heterogeneity in methods, findings across studies were consistent. Clinical risk factors of bipolar disorder were early-onset panic attacks and disorder, separation anxiety and generalized anxiety disorders, conduct symptoms and disorder, ADHD, impulsivity and criminal behavior. LIMITATIONS Since risk factors identified in some prospective studies are predictive of other conditions besides bipolar disorder, these preliminary findings require replication, and their sensitivity, specificity and predictive value need to be assessed. CONCLUSIONS Clinical risk factors for bipolar disorder typically arise years prior to syndromal onset, include anxiety and behavioral disorders with unclear sensitivity and specificity. Prospectively identified clinical risk factors for bipolar disorder are consistent with retrospective and family-risk studies. Combining clinical risk factors with precursors and family-risk may improve early identification and timely and appropriate treatment of bipolar disorder.