Utpal Goswami

Carbamazepine and valproate monotherapy: feasibility, relative safety and efficacy, and therapeutic drug monitoring in manic disorder

Abstract Rationale: Search for alternatives to lithium therapy for mood disorders commenced with anticonvulsants, carbamazepine (CBZ) and valproic acid (VPA), in the late 1970s. The comparative safety and efficacy data of CBZ and VPA monotherapy in patients with bipolar disorder remain to be established. Objectives: The main objectives of the study were to assess the relative anti-manic efficacy and safety of CBZ and VPA; to study the feasibility of using either, as a first line anti-manic agent; to investigate and generate clinically relevant parameters involving therapeutic drug monitoring of the two drugs. Methods: After a 2-day screening period, suitable patients (n=30) were randomly assigned to treatment with CBZ or VPA. Both the drugs were started with an average dose of approximately 20 mg/kg body weight per day. Further increment in dose was carried out at weekly intervals, guided by clinical improvement, serum levels and treatment emergent adverse events. The primary efficacy measure in the protocol was defined as a change from baseline to endpoint in total score on the Young Mania Rating Scale. A favourable clinical response was defined a priori as a decrease of more than 50% from baseline in Young Mania Rating Scale total score. Results: Both CBZ and VPA were found to be efficacious as single first-line anti-manic agents, however VPA proved to be better. Using the intent-to-treat analysis, the VPA group showed a significant fall in YMRS total scores after week 1 while the CBZ group showed a significant fall after week 2. In the primary efficacy analysis, valproate group experienced significantly greater mean improvement in Young Mania Rating Scale total score than the CBZ group. Of the VPA treated patients, 73% showed a favourable clinical response while 53% of the patients on CBZ responded favourably. In the CBZ group, significantly more patients received rescue medication during the week 2 and the requirement was quantitatively more as compared to the VPA group. The steady state serum concentration (Css) of CBZ ranged from 3 to 9 µg/ml; however, it did not appear to correlate with the dose or clinical response. The Css of VPA ranged from 50 to 100 µg/ml; a linear correlation was found between the dose and serum levels of VPA as well as between weekly rise in serum levels and clinical response. Weekly dose escalations of VPA also correlated positively with corresponding rise in serum levels. Significantly more patients in the CBZ group reported adverse events, including nausea, vomiting and dizziness, than VPA. Conclusions: The findings from this study suggest that both CBZ and VPA monotherapy is feasible for treatment of acute mania; however, VPA is more efficacious in terms of its early onset of action, lesser requirement for rescue medication and better tolerability. Further work needs to be undertaken to characterise the manic patients in terms of their differential psychopharmacologic response profile.

The neurocognitive performance of drug-free and medicated euthymic bipolar patients do not differ

Objective:  Although it is established that euthymic bipolar patients have neurocognitive deficits, the influence of medication on their cognitive performance is uncertain and requires investigation.

Pharmacokinetics of valproic acid in patients with bipolar disorder

The pharmacokinetics of valproic acid (VPA) were studied in nine patients with bipolar disorder who were receiving VPA as prophylactic therapy, following the full daily dose (400–1500 mg), on which the patients had been maintained for at least the past 3 months. The data from our study showed that the pharmacokinetics of valproate followed a two compartment open model. A time lag of 1–2 h was observed in each patient, followed by rapid absorption, with the peak concentrations being recorded approximately 4 h after drug administration. The average 12 h trough concentration was found to be 54.73 ± 11.96 µg/ml. The plasma level decline was biphasic with a terminal half-life of 14.2 ± 6.39 h. Total plasma clearance was 0.095 ± 0.035 ml/min/kg. The steady-state apparent volume of distribution was found to be 0.11 ± 0.05 l/kg. A positive correlation (r= 0.69) was found between the dose (mg/kg) and steady-state serum concentration (Css) of VPA and all patients, except one, had their Css above 50 µg/ml. Most of the pharmacokinetic parameters in this study involving euthymic bipolar patients on long-term VPA monotherapy were found to be in agreement with those reported in literature on seizure disorder patients on similar regime; however, the plasma elimination half-life appears to be prolonged in bipolar patients.

A Study of the Temporal Course of Phenomenology of Alcohol Dependence

The natural history of alcoholism was first charted out in 1946 by Jellinek, whose original results have been replicated by multiple research groups. They have verified a general progression of alcohol dependence through a series of identifiable phases. The study investigated the sequence of events in the course of alcohol dependence and its deviations from randomness. The study consisted of 36 patients with alcohol dependence, subjected to a structured questionnaire containing 34 items describing the phenomenology of alcohol dependence, based on the lines of SCID. The items experienced by each patient were identified and then plotted on a timeline graph according to an important life event, the items being represented on cards given to the patients randomly. The subjects were re-interviewed after one week and asked to rank their symptoms again to analyze test-retest reliability. The analysis of the item ordering was determined by null hypothesis of randomness. The ordering showed three phases. The early phase was characterized by features of increased tolerance loss of flexibility, and salience. The middle phase consisted mainly of the need for alcohol, and the late phase was predominated by features of physiological withdrawal, tremors, nausea, panics, and hallucinations. There is a characteristic ordering of new events and symptoms, which suggests a developmental process of alcoholism, but this is apparent only if attention is confined to a limited part of the broad spectrum. This process is obscured by consideration of the social concomitants of alcohol dependence. The study of the natural history of alcohol dependence is essential in recognizing and treating the problem and determining whether an intervention appears to be working.

Soft neurological signs in the first-degree relatives of subjects with bipolar-1 disorder

Introduction: Comorbid psychiatric diagnoses such as panic disorder and drug and alcohol abuse are common in both major depressive disorder (MDD) and bipolar disorder (BD). Although screening instruments such as the Hypomania Checklist (HCL-32) may be useful in distinguishing between bipolar and unipolar patients, very little work has assessed whether comorbidities, for example, substance abuse, may be related to ratings of hypomanic symptoms on such instruments. In this study we assess whether a lifetime diagnosis of comorbid panic disorder, drug abuse, alcohol abuse or alcohol dependence in patients with MDD is associated with increased ratings of hypomanic symptoms on the HCL-32. Methods: 50 patients with MDD (according to DSM-IV) recruited from out-patient psychiatric services were assessed for a range of diagnoses according to the Mini International Neuropsychiatric Interview (MINI). Subjects also completed a detailed structured clinical assessment and the HCL-32 questionnaire. A number of previous reports have found that a score of 14 or more on the HCL-32 is an optimal threshold for the correct identification of bipolar disorder (with a sensitivity of 80% and specificity 51%) so this threshold was applied to our sample of MDD patients. Two groups were identified according to whether they scored above or below 14 on the HCL-32 and were compared on rates on lifetime comorbid diagnosis of panic disorder, drug abuse, alcohol abuse and alcohol dependence. Results: 27 out of 50 MDD patients (54%) scored above the threshold of 14 or more on the HCL-32. There were no significant differences between these subjects and subjects not meeting the threshold on rates of comorbid panic disorder (48.1% versus 47.8%; OR = 1.01, 95%CI 0.60–1.68), drug abuse (7.4% versus 4.3%; OR = 1.25, 95%CI 0.54–2.92) or alcohol abuse (37.0% versus 21.7%; OR = 1.37, 95%CI 0.84–2.25). However, subjects scoring above the threshold had significantly higher rates of comorbid alcohol dependence (18.5% versus 0%; OR = 2.05, 95%CI 1.52–2.76). Discussion: 54% of MDD patients in this sample scored above the threshold of 14 on the HCL-32, suggestive of a bipolar diagnosis. Cormorbid alcohol dependence was significantly associated with scoring above the threshold. In fact, all of the MDD patients in this sample who also had a lifetime history of alcohol dependence scored 14 or more on the HCL-32. Future studies involving screening measures for bipolar disorder, particularly the HCL-32, should carefully consider the role played by comorbidities such as alcohol dependence.

REM sleep latency and neurocognitive dysfunction in schizophrenia.

Background: Cognitive deficits—the hallmark of schizophrenic deterioration—still remain elusive as far as their pathophysiology is concerned. Various neurotransmitter systems have been implicated to explain these deficits. Abnormalities in cholinergic neurotransmission in the brain are one of the postulations; acetylcholine has also been postulated to regulate rapid eye movement (REM) sleep, especially REM latency. Thus, REM latency in patients with schizophrenia might provide a non-invasive window to look into the cholinergic functions of the brain. Aim: To study REM sleep measures and neurocognitive function in schizophrenia, and the changes occurring in these parameters following pharmacological treatment. Methods: Thirty subjects (15 with schizophrenia and 15 normal non-relative controls) were evaluated in this study. Most patients with schizophrenia had prominent negative symptoms and deficits in the performance in neurocognitive tests battery. They were treated with antipsychotics for a variable period of time and post-treatment evaluation was done using the same battery of neurocognitive tests and polysomnography. Patients were either drug-naïve or kept drug-free for at least two weeks both at baseline as well as at the post-treatment stage. Results: A positive correlation between the severity of negative symptoms and neurocognitive deficits (especially on the Wisconsin Card Sorting), and a negative correlation between these two parameters and REM latency was observed. Conclusion: It can be hypothesized that the acetylcholine deficit model of dementia cannot be applied to schizophrenic dementia, rather a hypercholinergic state results. This state warrants anticholinergic medication as a treatment option for negative symptoms of schizophrenia.