Alessandra Benedetti

L-type calcium channels and psychiatric disorders: A brief review†‡

Emerging evidence from genome‐wide association studies (GWAS) support the association of polymorphisms in the alpha 1C subunit of the L‐type voltage‐gated calcium channel gene (CACNA1C) with bipolar disorder. These studies extend a rich prior literature implicating dysfunction of L‐type calcium channels (LTCCs) in the pathophysiology of neuropsychiatric disorders. Moreover, calcium channel blockers reduce Ca2+ flux by binding to the α1 subunit of the LTCC and are used extensively for treating hypertension, preventing angina, cardiac arrhythmias and stroke. Calcium channel blockers have also been studied clinically in psychiatric conditions such as mood disorders and substance abuse/dependence, yielding conflicting results. In this review, we begin with a summary of LTCC pharmacology. For each category of disorder, this article then provides a review of animal and human data. In particular, we extensively focus on animal models of depression and clinical trials in mood disorders and substance abuse/dependence. Through examining rationale and study design of published clinical trials, we provide some of the possible reasons why we still do not have definitive evidence of efficacy of calcium‐channel antagonists for mood disorders. Refinement of genetic results and target phenotypes, enrollment of adequate sample sizes in clinical trials and progress in physiologic and pharmacologic studies to synthesize tissue and isoform specific calcium channel antagonists, are all future challenges of research in this promising field.

Oxcarbazepine as add-on treatment in patients with bipolar manic, mixed or depressive episode.

OBJECTIVES The aim of this preliminary open-label trial was to evaluate the efficacy and safety of oxcarbazepine (OXC) as adjunctive therapy in 18 patients with bipolar disorder who did not respond satisfactorily to lithium. METHODS Eighteen patients with bipolar I (n=16) and bipolar II (n=2) disorder were treated openly with OXC for a 8-week period as add-on treatment to the existing lithium regimen. After the 8-week trial, all patients continued the treatment with OXC, and were followed-up prospectively. Outcome measures included the Clinical Global Impression-Bipolar Version Scale, the Bech-Rafaelsen Mania-Melancholia Scale and the Brief Psychiatric Rating Scale. These scales were administered at baseline and at the end of weeks 2, 4 and 8. Patients were subsequently assessed every 4 months for a period of time ranging from 4 to 12 months with the Longitudinal Interval Follow-up Evaluation. RESULTS The mean dose of OXC at the end of week 8 was 919.4 mg/day (SD+/-335.7). Eleven of the 18 patients were considered responders. The remaining seven patients were rated as nonresponders. Of the eleven responders to the 8-week trial, seven patients remained mood-stabilized for the entire period of follow-up. CONCLUSIONS OXC appeared to be significantly effective as add-on strategy in 60% of patients after 8 weeks of treatment. A substantial proportion (66.3%) of the 8-week trial responders maintained a satisfactory mood stabilization during the follow-up. Despite several limitations, our study suggests the potential usefulness of OXC as adjunctive therapy to lithium both in acute and long-term treatment of bipolar disorder.

Delineating a putative phobic-anxious temperament in 126 panic-agoraphobic patients: toward a rapprochement of European and US views.

BACKGROUND The current US official position, since DSM-III, is that panic attacks represent the hallmark of panic disorder and play a major role in the development of the agoraphobic syndrome. The more favoured view in the European tradition is that neurotic personality and/or prodromal features such as mild depression and excessive worries precede the illness. METHOD We studied 126 consecutive cases of panic disorder with or without agoraphobia by DSM-III-R criteria, evaluated by relevant structured and semi-structured interviews. RESULTS We provide evidence that characterological and prodromal antecedents represent a putative phobic-anxious temperamental substrate occurring in at least 30% of our sample. This temperament consists of three or more of the following traits: (1) increased sympathetic activity with repeated sporadic and isolated autonomic manifestations; (2) marked fear of illness; (3) hypersensitivity to separation; (4) difficulty to leave familiar surroundings; (5) marked need for reassurance; (6) oversensitivity to drugs and substances. Our data further suggest that these attributes are of familial origin, as a result of which the illness tends to declare itself earlier. LIMITATION The present investigation is largely correlational without a prospective component; however, the key validating familial data were obtained blindly. CONCLUSION Our data support a pathogenetic model whereby genetic diathesis unfolds from subclinical to clinical manifestations along temperamental, panic, phobic and avoidant patterns. We submit that the delineation of the phobic-anxious temperament will be useful in more completely charting the life course of the panic-agoraphobic spectrum; avoidant and dependent (Axis II) patterns appear more distal in the pathogenetic chain and, in many cases, can be conceptualized to be epiphenomenal to the disease process.

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.

Hypochondriasis and illness phobia in panic-agoraphobic patients

In a sample of 131 patients with panic disorder, we explored both the presence of DSM-III-R criteria for hypochondriasis and the occurrence of illness phobia before the onset of panic disorder. To explore further the possible relationship between hypochondriacal features and panic-agoraphobic syndrome, we compared patients both with and without current hypochondriasis and then patients both with and without illness phobia before the onset of panic disorder. Finally, we investigated the relationship between premorbid phobic-anxious traits and hypochondriasis during panic disorder. No differences were found between patients with and without hypochondriasis, either in terms of clinical features or in the course of panic disorder. Patients with illness phobia before the onset of panic disorder reported higher levels of anticipatory anxiety in nonagoraphobic situations and more depersonalization and derealization during panic attacks, and they met our definition of phobic-anxious temperament more frequently than the rest of the sample. This would suggest that illness phobia before the onset of panic disorder may be viewed either as a separate disorder, a prodrome, or a mild, early-onset form of panic disorder without full-blown attacks. Although patients with premorbid illness phobia are more likely to develop hypochondriasis after the onset of panic disorder, approximately 40% of them do not; therefore, illness phobia should not be considered the only factor that influences the development of hypochondriasis during panic disorder.

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.

Onset polarity and illness course in bipolar I and II disorders: The predictive role of broadly defined mixed states

Several studies investigating bipolar disorders have shown that polarity of onset can predict differences in symptomatology, course, and prognosis. Frequently, however, research on the topic has examined only bipolar I inpatients and has not included patients with mixed onset. The aim of the present naturalistic study was to evaluate the clinical characteristics and illness course of a consecutive sample (407 outpatients, 58.7% with bipolar I (BD-I) and 41.3% with bipolar II (BD-II) disorder) according to polarity of onset: depressive (DP-o); manic/hypomanic (HM-o); or mixed--broadly defined to include agitated depression for BD-II--onset (MX-o). As compared with patients in the other two groups: a) DP-o patients (67.3%) were more frequently affected by BD-II and had lower ratings for psychotic symptoms; b) HM-o patients (17%) had a higher rate of family history for psychosis and a lower rate of suicide attempts; and c) patients in the MX-o group (15.7%) more frequently showed substance abuse and had a higher number of mixed recurrences per year. In the BD-II group, MX-o patients more frequently attempted suicide. The present studys main limitations are those of retrospective assessment of onset polarity and lack of treatment-impact evaluations over illness course. In conclusion, we confirm clinical expression differences in bipolar disorder in function of polarity of onset and underscore the importance of carefully considering broadly defined mixed state when examining polarity of onset. Further investigations are required to confirm the present studys results.

Predictors of recurrence during long-term treatment of bipolar I and II disorders. A 4 year prospective naturalistic study

BACKGROUND Despite the large number of treatments available for bipolar disorder (BD), more than one half of patients have a recurrence within 2 years, and over 90% experience at least one additional affective episode during their lifetime. METHODS The aim of this study was to test the impact of a number of demographic and clinical features on the risk to recurrence in a real- word representative sample of 266 outpatients with BD-I or II treated in a naturalistic setting during a 4-years-follow-up period. RESULTS We found that the number of episodes per year after study entry, compared to the number of episodes per year before study entry,significantly decreased and that about one third of patients had no recurrences during the observation period. The length of follow-up and the number of previous episodes, mainly depressive, predicted the risk of recurrence, while female gender, higher age at intake, and a higher frequency of past mixed episodes predicted a higher frequency of recurrences. LIMITATIONS The study had some limitations to consider: i.e. the risk of poor reliability of information on the previous course of illness or the naturalistic treatment during the follow-up. CONCLUSIONS Our study suggests that (a) an evidence-based long-term treatment, with regular follow-up visits could improve the course of disease and prognosis; (b) clinicians should carefully consider the presence of a high number of mixed episodes, to provide more targeted treatment strategies; (c) an appropriate use of antidepressants in selected patients did not worsen the course of illness.

Lithium, valproate, and carbamazepine prescribing patterns for long-term treatment of bipolar I and II disorders: A prospective study

This study aims to describe the prescription patterns of the mood stabilizers most commonly used for the treatment of bipolar I and II disorders (lithium, valproate, and carbamazepine) and to analyze the treatment outcomes.