Giulia Serra

Suicidal behavior and alcohol abuse

Suicide is an escalating public health problem, and alcohol use has consistently been implicated in the precipitation of suicidal behavior. Alcohol abuse may lead to suicidality through disinhibition, impulsiveness and impaired judgment, but it may also be used as a means to ease the distress associated with committing an act of suicide. We reviewed evidence of the relationship between alcohol use and suicide through a search of MedLine and PsychInfo electronic databases. Multiple genetically-related intermediate phenotypes might influence the relationship between alcohol and suicide. Psychiatric disorders, including psychosis, mood disorders and anxiety disorders, as well as susceptibility to stress, might increase the risk of suicidal behavior, but may also have reciprocal influences with alcohol drinking patterns. Increased suicide risk may be heralded by social withdrawal, breakdown of social bonds, and social marginalization, which are common outcomes of untreated alcohol abuse and dependence. People with alcohol dependence or depression should be screened for other psychiatric symptoms and for suicidality. Programs for suicide prevention must take into account drinking habits and should reinforce healthy behavioral patterns.

Antidepressant-associated mood-switching and transition from unipolar major depression to bipolar disorder: A review

OBJECTIVES Compare reported rates of mood-shifts from major depression to mania/hypomania/mixed-states during antidepressant (AD)-treatment and rates of diagnostic change from major depressive disorder (MDD) to bipolar disorder (BPD). METHODS Searching computerized literature databases, followed by summary analyses. RESULTS In 51 reports of patients diagnosed with MDD and treated with an AD, the overall risk of mood-switching was 8.18% (7837/95,786) within 2.39 ± 2.99 years of treatment, or 3.42 (95% CI: 3.34-3.50) %/year. Risk was 2.6 (CI: 2.5-2.8) times greater with/without AD-treatment by meta-analysis of 10 controlled trials. Risk increased with time up to 24 months of treatment, with no secular change (1968-2012). Incidence rates were 4.5 (CI: 4.1-4.8)-times greater among juveniles than adults (5.62/1.26 %/year; p<0.0001). In 12 studies the overall rate of new BPD-diagnoses was 3.29% (1928/56,754) within 5.38 years (0.61 [0.58-0.64] %/year), or 5.6-times lower (3.42/0.61) than annualized rates of mood-switching. CONCLUSIONS AD-treatment was associated with new mania-like responses in 8.18% of patients diagnosed with unipolar MDD. Contributions to mood-switching due to unrecognized BPD versus mood-elevating pharmacological effects, as well as quantitative associations between switching and later diagnosis of BPD not associated with AD-treatment remain uncertain. LIMITATIONS Rates and definitions of mood-switching with ADs varied greatly, exposure-times rarely were precisely defined, and there was little information on predictive associations between mood-switches and BPD-diagnosis.

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.

Rapid cyclers and antidepressants.

434 bipolar manic-depressive patients were followed longitudinally. The course of the disease changed in many patients over the years. 67 cases became rapid cyclers (two or more cycles per year); in 40 of these cases (12 men and 28 women) the change of the course took place after intense or protracted use of antidepressant drugs. In their previous course these patients had not received antidepressant drugs. The common feature of the transformation of the previous course to a continuous circular one was the appearance for the first time in the course of the disease of hypomanic episodes after the depressions, or the accentuation of hypomanias that had been of milder intensity in previous recurrences. The patients who developed continuous circularity under antidepressant drug treatment were of highly energetic temperament. The hypothesis is advanced that these patients have latent hypomanias, which become clinically manifest under the action of antidepressants. The intensification of an underlying hypomanic process by the antidepressants would precipitate another depression and establish continuous circularity. The change to a rapid cyclical course was more frequent in middle-aged patients and in women.

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.

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.

The wnt pathway in mood disorders

Objectives: To review the evidence of the involvement of the Wnt signalling pathway in mood disorders and in the action of drugs used to treat these disorders. Methods: We performed a careful PubMed search using as keywords all possible terms relevant to the Wnt pathway and crossing them with each of four areas, i.e., developmental effects, behavioural effects, mood disorders, and drugs used in their treatment. Papers were selected on the basis of their content and their data used for discussion. Results: Neurodevelopmental and behavioural data point to the possibility of involvement of the Wnt pathway in the pathophysiology of mood disorders. Clinical and post-mortem data are not sufficient to corroborate a definite role for Wnt alterations in any mood disorder. Combining genetic and pharmacological data, we may state that glycogen synthase kinase is the key molecule in bipolar disorder, as it is connected with many other signalling pathways that were shown to be involved in mood disorders, while Wnt molecules in the hippocampus appear to be mainly involved in depressive disorders. Conclusions: Altered Wnt signalling may play a role in the pathophysiology of mood disorders, although not a central one. It is premature to draw conclusions regarding the possible usefulness of Wnt manipulations in the treatment of mood disorders.

Re-examining the risk for switch from unipolar to bipolar major depressive disorder in youth with ADHD: A long term prospective longitudinal controlled study

BACKGROUND Recent studies have identified subthreshold forms of bipolar (BP)-I disorder and deficits in emotional regulation as risk factors for bipolar disorder in youth. The primary aim of this study was to investigate whether emotional dysregulation and subthreshold forms of BP-I disorder increase the risk for BP switches in ADHD youth with non-bipolar MDD. METHODS We used data from two large controlled longitudinal family studies of boys and girls with and without ADHD. Subjects (N=522) were followed prospectively and blindly over an average follow up period of 11.4 years. Comparisons were made between ADHD youth with unipolar major depression (MDD) who did (N=24) and did not (N=79) switch to BP-I disorder at follow-up. RESULTS The rate of conversion to BP-I disorder at follow up was higher in MDD subjects with subthreshold BP-I disorder at baseline compared to those without (57% vs. 21%; OR=9.57, 95% CI=1.62-56.56, p=0.013) and in MDD subjects with deficient emotional self-regulation (OR=3.54, 95% CI=1.08-11.60, p=0.037). LIMITATIONS The sample was largely Caucasian, so these results may not generalize to minority groups. The sample of youth with SED was small, which limited the statistical power for some analyses. CONCLUSIONS Switches from unipolar MDD to BP-I disorder in children with ADHD and MDD were predicted by baseline subthreshold BP-I disorder symptoms and baseline deficits in emotional regulation. More work is needed to assess whether these risk factors are operant outside the context of ADHD.

Patient outcome in migraine prophylaxis: the role of psychopharmacological agents

Introduction: Migraine is a serious illness that needs correct treatment for acute attacks and, in addition, a treatment prophylaxis, since patients with migraine suffer during acute attacks and also between attacks. Methods: A systematic review of the most relevant clinical trials of migraine headache and its epidemiology, pathophysiology, comorbidity, and prophylactic treatment (medical and nonmedical) was carried out using “Medline” and “PsychINFO” from 1973 to 2009. Approximately 110 trials met our inclusion criteria and were included in the current review. Results: The most effective pharmacological treatment for migraine prophylaxis is propranolol and anticonvulsants such as topiramate, valproic acid, and amitriptyline. Nonmedical treatments such as acupuncture, biofeedback, and melatonin have also been proposed. Peripheral neurostimulation has been suggested for the treatment of chronic daily headache that does not respond to prophylaxis and for the treatment of drug-resistant primary headache. The majority of the pharmacological agents available today have limited efficacy and may cause adverse effects incompatible with long-term use. Limitations: The review was limited by the highly variable and often insufficient reporting of the complex outcome data and by the fact that migraine prophylaxis trials typically use headache diaries to monitor the course of the disease. The results of the different studies were also presented in different ways, making comparison of the results difficult. Discussion: An adequate prophylaxis is crucial in reducing disability and preventing the evolution of the problem into a chronic progressive illness. The implications of the present findings were discussed.