Francesco Casamassima

Phenotypic effects of a bipolar liability gene among individuals with major depressive disorder.

Variations in voltage‐dependent calcium channel L‐type, alpha 1C subunit (CACNA1C) gene have been associated with bipolar disorder in a recent meta‐analysis of genome‐wide association studies [Ferreira et al., 2008 ]. The impact of these variations on other psychiatric disorders has not been yet investigated. Caucasian non‐Hispanic participants in the STAR*D study of treatment for depression for whom DNA was available (N = 1213) were genotyped at two single‐nucleotide polymorphisms (SNPs) (rs10848635 and rs1006737) in the CACNA1C gene. We examined putative phenotypic indicators of bipolarity among patients with major depression and elements of longitudinal course suggestive of latent bipolarity. We also considered remission and depression severity following citalopram treatment. The rs10848635 risk allele was significantly associated with lower levels of baseline agitation (P = 0.03; β = −0.09). The rs1006737 risk allele was significantly associated with lesser baseline depression severity (P = 0.04; β = −0.4) and decreased likelihood of insomnia (P = 0.047; β = −0.22). Both markers were associated with an increased risk of citalopram‐emergent suicidality (rs10848635: OR = 1.29, P = 0.04; rs1006737: OR = 1.34, P = 0.02). In this exploratory analysis, treatment‐emergent suicidality was associated with two risk alleles in a putative bipolar liability gene.

Gender differences in bipolar disorder type 1: a 48-week prospective follow-up of 72 patients treated in an Italian tertiary care center.

To explore gender differences in bipolar I disorder, we compared the longitudinal treatment outcome and baseline demographic and clinical characteristics of 27 male and 45 female adult subjects who were treated for an acute affective episode and longitudinally followed for a period of up to 48 weeks. Females were more likely to report a history of suicidal gestures and a comorbid panic disorder; males were more likely to present with a comorbid obsessive-compulsive disorder, and there was a trend for a more frequent history of alcohol or substance abuse. No significant differences were found between the genders for the time to remission from the index episode, number of recurrences, and time spent with any clinical or subclinical mood symptom during the 48 weeks of maintenance treatment. Although differences may exist between bipolar I male and female subjects, prospective course does not seem to reveal differences in a 48-week period, at least when similar treatment strategies are adopted.

Catatonia and neuroleptic malignant syndrome: two disorders on a same spectrum? Four case reports.

Abstract We present the history of four bipolar patients who developed neuroleptic malignant syndrome (NMS) after antipsychotic treatment, focusing on the relationship between NMS and catatonia. In all cases, the administration of antipsychotics has been suspended as soon as fever and autonomic disturbances occurred. A supportive therapy was initiated to stabilize general conditions, then every patient started electroconvulsive therapy (ECT) in combination with benzodiazepines (BDZ). The risk of complications was reduced by the quick adoption of supportive care, whereas the combination of ECT and BDZ was effective in resolving the clinical picture. These cases may provide further support to the hypothesis that catatonia and NMS are disorders pertaining to the same spectrum of illness because the onset or exacerbation of catatonic symptoms coincided with the administration of antipsychotics. Our experience confirms the efficacy and safety of ECT in combination with BDZ as treatment of NMS and residual catatonia.

Augmentation of Clozapine with Aripiprazole in Severe Psychotic Bipolar and Schizoaffective Disorders: A Pilot Study

Aim: To evaluate the efficacy and safety of the augmentation of clozapine with aripiprazole in patients with treatment-resistant schizoaffective and psychotic bipolar disorders in a retrospective manner. Pharmacodynamic and pharmacokinetic interactions between the two drugs were also investigated. Patients: Three men and 4 women (median age 36 and 40 years, respectively) who had mean scores at BPRS and CGI-Severity of 59.1±12.0 and 5.4±0.5, respectively, were treated with clozapine (mean dose 292.9±220.7 mg/day). Patients received an adjunctive treatment with aripiprazole (mean dose 6.8 ± 3.7 mg/day). Clozapine, norclozapine and aripiprazole plasma levels were measured by means of a high performance liquid chromatograpy with UV detection. Results: Total scores at BPRS decreased significantly (from 59.1±12.0 to 51.1±15.6, p=0.007) after aripirazole augmentation. In particular, the factors “thought disorder” (from 10.4±4.4 to 9.0±4.5, p=.047) and “anergia” (from 10.0±2.7 to 8.0±2.4, p=.018) significantly improved. Concomitant administration of aripiprazole and clozapine did not result in an increase in side effects over the period of treatment. Dose-normalized plasma levels of both clozapine and norclozapine and the clozapine/norclozapine metabolic ratio in all patients did not vary as well. Conclusion: The augmentation of clozapine with aripirazole was safe and effective in severe psychotic schizoaffective and bipolar disorders which failed to respond to atypical antipsychotics. A possible pharmacokinetic interaction between clozapine and aripiprazole does not account for the improved clinical benefit obtained after aripiprazole augmentation.

Neuroleptic malignant syndrome: further lessons from a case report.

Background Neuroleptic malignant syndrome (NMS) represents an iatrogenic form of malignant catatonia, and simple catatonia has been shown to predispose to NMS. Objective The authors present the case of a bipolar patient with catatonic features who developed NMS after receiving haloperidol. Method Supportive therapy, including rehydration, electrolyte restoration, and blood pressure aids were given, together with antipyretics, antibiotics, and anticoagulants. The patient was also started on bromocriptine and diazepam. Results Supportive care, diazepam, and dopamine agonists yielded only partial benefit. However, switching from diazepam to lorazepam, in combination with electroconvulsive therapy (ECT) and a long-acting dopamine agonist led to the resolution of NMS. Conclusion This case sheds further light on the relationship between catatonia and NMS. As noted in the literature, ECT in combination with lorazepam proved to be safe and effective for NMS.

Stability of symptoms across major depressive episodes in bipolar disorder

OBJECTIVE Some studies suggest that depressive subtypes, defined by groups of symptoms, have predictive or diagnostic utility. These studies make the implicit assumption of stability of symptoms across episodes in mood disorders, which has rarely been investigated. METHODS We examined prospective data from a cohort of 3,750 individuals with bipolar I or II disorder participating in the Systematic Treatment Enhancement Program for Bipolar Disorder study, selecting a subset of individuals who experienced two depressive episodes during up to two years of follow-up. Across-episode association of individual depressive or hypomanic/mixed symptoms was examined using the weighted kappa measure of agreement as well as logistic regression. RESULTS A total of 583 subjects experienced two prospectively observed depressive episodes, with 149 of those subjects experiencing a third. Greatest evidence of stability was observed for neurovegetative features, suicidality, and guilt/rumination. Loss of interest and fatigue were not consistent across episodes. Structural equation modeling suggested that the dimensional structure of symptoms was not invariant across episodes. CONCLUSION While the overall dimensional structure of depressive symptoms lacks temporal stability, individual symptoms including suicidality, mood, psychomotor, and neurovegetative symptoms are stable across major depressive episodes in bipolar disorder and should be considered in future investigations of course and pathophysiology in bipolar disorder.

Aripiprazole for the treatment of bipolar disorder: a review of current evidence

Introduction: Several medications are available for the treatment of different phases of bipolar disorder, yet many of the drugs that are currently approved carry a substantial burden of side effects or do not lead all treated patients to remission. Areas covered: This paper comprises a review and commentary regarding the use of oral and intramuscular aripiprazole in the acute and maintenance phases of bipolar disorder. Basic principles in dosing, switching, management of side effects and co-administration of aripiprazole with other medications are provided. This paper presents practical strategies to translate the data from clinical research into clinical practice. Expert opinion: Aripiprazole has proven to be an effective medication for the acute treatment of manic and mixed episodes, as well as for the prophylactic–maintenance phase of bipolar disorder in patients recovering from a manic/mixed episode. Choosing the appropriate dosing and tapering strategy, addressing the side effects, controlling withdrawal symptoms from previous medications and using adjunctive medications when necessary are key to successful treatment with aripiprazole.

Pharmacotherapy of binge-eating disorder: a review.

Objectives:The purpose of this article is to provide a comprehensive review of pharmacotherapy for binge eating disorder, including new therapeutic approaches such as centrally acting sympathomimetics, nootropics, lisdexamfetamine, and substance abuse treatment agents such as acamprosate, sodium oxybate, baclofen, and naltrexone. Methods:The study was conducted by searching the MEDLINE database using the keywords “binge eating disorder,” “obesity,” and “pharmacological therapy.”All available studies on each drug dating from 1988 to the present were considered, focusing mainly on randomized controlled trials (RCTs). Other types of studies were considered when no RCTs were found. We drafted separate tables for open-label studies (Table 1), RCT (Table 2), and retrospective studies (Table 3). Each study is detailed by the number of subjects, additional design considerations, doses, results, additional main comparators, and study limitations. Results:The data emerging from this study seem to show that, at least in the short term, some specific medications within the classes of antidepressants, anticonvulsants, and antiobesity agents may prove promising in achieving the main objectives in the treatment of binge eating disorder: reducing the frequency of binge eating, reducing weight, and improving the associated psychopathology. The major limitation in interpreting these results is the short duration of the studies and the lack of adequately sized trials, or trials including patients with medical comorbidities.Good results are being obtained with new combinations of drugs and with substance abuse treatment agents. Although the precise nature of the relationship between substance use disorders and binge eating disorder remains to be clarified, the evidence suggests that treatments recognized as effective for substance use disorders may be useful as novel treatments for binge eating disorder. This field of research remains open to future studies with more precise methodological approaches and more detailed parameter assessment; a multidisciplinary approach is also essential to better understand such a complex disease.

Asenapine for the treatment of manic and mixed episodes associated with bipolar I disorder: from clinical research to clinical practice

Introduction: Asenapine is a sublingually administered second-generation antipsychotic with proven efficacy for the treatment of moderate to severe manic episodes associated with bipolar I disorder in adults. Its relatively favorable weight and metabolic profile, as well as the lack of appreciable activity at muscarinic cholinergic receptors and the sublingual administration are of clinical interest. Areas covered: This paper comprises a review and commentary regarding the use of sublingual asenapine in the treatment of acute manic and mixed episodes of bipolar disorder. Basic principles in dosing, switching, management of side effects and co-administration with other medications are provided. Expert opinion: Asenapine displays quick and reliable effects on manic symptoms, very low risk of depressive switches, efficacy on depressive symptoms during manic and mixed episodes, usually good tolerability and continued longer-term efficacy on residual and subthreshold symptoms. The fast-dissolving sublingual route of administration may favor those who have difficulties in swallowing medications. Also, the sublingual administration reduces the risk of overdose when more than the prescribed tablets are swallowed. The relatively low metabolic risk and the lack of anticholinergic side effects contribute to making this medication a useful tool for the treatment of patients with bipolar disorder.

Risperidone long-acting injection as monotherapy and adjunctive therapy in the maintenance treatment of bipolar I disorder

Importance of the field: It is very rare for patients with bipolar disorder to have a single episode of mania or depression over a lifetime and the vast majority of these individuals need long-term prophylactic/maintenance treatment. However, treatment nonadherence is a major issue for close to half of subjects with bipolar disorder who are prescribed medications. Risperidone long-acting injection (LAI) has proven efficacious for the maintenance phase of bipolar disorder and may mitigate the problem of nonadherence in the substantial group of patients for whom this is a significant concern. Areas covered in this review: This paper comprises a review and commentary regarding the use of risperidone LAI in bipolar disorder. What the reader will gain: The reader will gain an understanding regarding the risks and benefits of risperidone LAI in bipolar disorder. We review the available evidence and discuss the strengths and weaknesses of published studies, providing an opinion about the clinical usefulness of risperidone LAI as well as suggestions for future research. Take home message: The use of risperidone LAI, through improved adherence, has the potential to ameliorate the course of bipolar disorder.