Lack of enhanced response to repeated d-amphetamine challenge in first-episode psychosis: implications for a sensitization model of psychosis in humans.

Behavioral sensitization is the process whereby intermittent stimulant exposure produces a time-dependent, enduring, and progressively more robust behavioral response. This process serves as a model for the development of psychosis, but has been little studied in humans. The authors report results from a double-blind, placebo-controlled study of repeated d-amphetamine challenges in 13 patients with first-episode manic or schizophrenic psychosis. Each patient received two daily doses of d-amphetamine (0.25 mg/kg) separated by 48 hours that alternated with two daily doses of matched placebo. Symptoms (activity/energy level, mood, rate and amount of speech, and severity of psychosis) and eye-blink rates were measured hourly for 5 hours following drug administration. In contrast to results from previous work in normal volunteers, none of the measures demonstrated the progressive increase following the second amphetamine dose as compared to the first dose that characterizes sensitization. These results suggest that patients with psychosis are already maximally sensitized, so cannot exhibit progressive behavioral enhancement following repeated stimulant challenges, or that patients with psychosis do not sensitize.

Differences in thyroid function between bipolar manic and mixed states.

BACKGROUND: High rates of thyroid axis abnormalities have been reported in most studies of patients with rapid-cycling bipolar disorder. Mixed states share similarities with rapid-cycling, including close temporal occurrence of manic and depressive symptoms, predominance in women, poor outcome, and less robust response to lithium compared with pure mania; however, thyroid axis abnormalities have not been well studied in mixed mania. METHODS: To test the hypothesis that mixed states are associated with a higher prevalence of hypothyroidism than pure mania, immunoreactive triiodothyronine (T3), thyroxine (T4), and thyroid-stimulating hormone (TSH) concentrations were determined from serum obtained at the time of admission in 37 consecutive patients with DSM-III-R bipolar disorder, manic or mixed. RESULTS: The mean TSH concentration was significantly higher, and the mean T4 concentration was significantly lower in patients with mixed mania compared with pure mania. There were no significant differences in T3 concentration or in previous lithium exposure. CONCLUSIONS: These findings suggest thyroid axis dysfunction is more common in bipolar mixed than in bipolar manic patients.

Symptom correlates of attentional improvement following hospitalization for a first episode of affective psychosis.

BACKGROUND: This study examined patients with a first-episode of affective psychosis during acute and compensated states in order to determine whether changes in attentional functioning over time were accompanied by changes in the severity of psychotic or affective symptoms. METHODS: Attentional performance was measured in patients (n = 27) using the degraded-stimulus continuous Performance Test (CPT) and symptoms were assessed at the time of index hospitalization, and 2 months after discharge. A comparison group of normal volunteers (n = 31) also performed the CPT two months apart. RESULTS: Patients performed significantly worse than controls at the initial testing but not at follow-up. The improvement in attentional performance significantly correlated with decreased severity of manic symptoms. CONCLUSIONS: Results suggest attentional dysfunction is a state-dependent characteristic of mania, and may provide an additional measure of clinical improvement following treatment.

A pharmacoeconomic model of divalproex vs. lithium in the acute and prophylactic treatment of bipolar I disorder.

BACKGROUND: Divalproex and lithium are the two most rigorously studied pharmacologic treatments for acute mania in bipolar I disorder in randomized, controlled trials. The differences between the drugs in their time course of onset, predictors of response, and side effects have potentially important pharmacoeconomic implications. METHOD: Utilizing data from published studies, the University of Cincinnati Mania Project, and a consensus panel of psychiatrists, we developed a decision-analytic model to estimate the costs of treating patients with bipolar I disorder, acutely and prophylactically, for 1 year with divalproex or lithium. RESULTS: In the overall group of patients with bipolar I disorder, initial treatment with divalproex led to costs that were 9% lower than costs for initial treatment with lithium. Cost savings associated with divalproex were greatest for patients with mixed mania and rapid cycling, whereas cost savings for patients with classic mania were greater for lithium. CONCLUSION: According to the decision-analytic model developed in this study, divalproex, possibly because of a more rapid rate of antimanic activity associated with oral loading, is a less costly treatment than lithium in the acute and prophylactic treatment of patients with bipolar I disorder over 1 year.

A randomized comparison of divalproex oral loading versus haloperidol in the initial treatment of acute psychotic mania.

BACKGROUND: Uncontrolled evidence suggests that divalproex administered via the oral loading strategy of 20 mg/kg/day may produce clinically significant antimanic response within 3 days of treatment in some patients. We conducted a prospective study to compare the antimanic response of divalproex oral loading with that of haloperidol in the initial treatment of acute psychotic mania. METHOD: After a < or = 1-day screening period, 36 consecutive hospitalized patients with bipolar disorder, manic or mixed phase and with psychotic features, were randomly assigned to receive either divalproex 20 mg/kg/day or haloperidol 0.2 mg/kg/day for 6 full days, without other psychotropic agents except lorazepam up to 4 mg/day for management of agitation. Serum valproate concentrations were measured after 1 day of treatment. Response was measured daily by a blind rater using the Young Mania Rating Scale and the Scale for Assessment of Positive Symptoms. RESULTS: Divalproex oral loading and haloperidol were equally effective in acutely reducing manic and psychotic symptoms. The greatest rate of improvement for both drug regimens occurred over the first 3 full days of treatment. Side effects were infrequent and minor for both treatments, except for extrapyramidal side effects which were significantly more common with haloperidol. CONCLUSION: Divalproex oral loading may produce rapid onset of antimanic and antipsychotic response comparable to that of haloperidol and with minimal side effects in the initial treatment of acute psychotic mania in a subset of bipolar patients.

Factors associated with pharmacologic noncompliance in patients with mania.

BACKGROUND: Studies of noncompliance with pharmacotherapy in bipolar disorder have primarily involved outpatients receiving lithium. There are limited data to date regarding the rates of noncompliance in patients with bipolar disorder and schizoaffective disorder hospitalized for recurrent mania. Similarly, the influence of race, illness phenomenology, and comorbid psychiatric and medical disorders and the treatment with antipsychotics, antidepressants, and mood-stabilizing agents other than lithium on noncompliance in this population have not been systematically examined. METHOD: Patients hospitalized for acute mania (N = 101) were evaluated by the Structured Clinical Interview for DSM-III-R to establish diagnosis and comorbidity and the Young Mania Rating Scale and Hamilton Rating Scale for Depression to assess severity of manic and depressive symptoms, respectively. Compliance was assessed by responses to a clinician-administered questionnaire administered to the patient, treaters, and significant others and by admission plasma concentrations of mood-stabilizing agents. RESULTS: Sixty-five patients (64%) were noncompliant with their pharmacologic regimen in the month prior to admission as defined by criteria for full compliance and partial or total noncompliance. Noncompliance was significantly associated with greater severity of mania upon admission (p = .02) and treatment with combinations of mood stabilizers (p = .01). CONCLUSION: Noncompliance with pharmacotherapy was present in the majority of patients admitted for acute mania and was associated with greater severity of mania upon admission and treatment with combinations of mood stabilizers.

A risk-benefit assessment of pharmacological treatments for panic disorder.

Panic disorder, a psychiatric disorder characterised by frequent panic attacks, is the most common anxiety disorder, affecting 2 to 6% of the general population. No one line of treatment has been found to be superior, making a risk-benefit assessment of the treatments available useful for treating patients. Choice of treatment depends on a number of issues, including the adverse effect profile, efficacy and the presence of concomitant syndromes. Tricyclic antidepressants (TCAs) are beneficial in the treatment of panic disorder. They have a proven efficacy, are affordable and are conveniently administered. Adverse effects, including jitteriness syndrome, bodyweight gain, anticholinergic effects and orthostatic hypotension are commonly associated with TCAs, but can be managed successfully. Selective serotonin (5-hydroxytryptamine; 5HT) reuptake inhibitors are also potential first line agents and are well tolerated and effective, with a favourable adverse effects profile. There is little risk in overdose or of anticholinergic effects. Adverse effects include sedation, dyspepsia and headache early in treatment, and sexual dysfunction and increased anxiety, but these can be effectively managed with proper dosage escalation and management. Benzodiazepines are an effective treatment, providing short-term relief of panic-related symptoms. Patients respond to treatment quickly, providing rapid relief of symptoms. Adverse effects include ataxia and drowsiness, and cognitive and psycho-motor impairment. There are reservations over their first-line use because of concerns regarding abuse and dependence. Monoamine oxidase inhibitors, because of their adverse effects profile, potential drug interactions, dietary restrictions, gradual onset of effect and overdose risk, are not considered to be first-line agents. They are effective however, and should be considered for patients with refractory disease. Valproic acid (valproate sodium), while not intensively studied, shows potential for use in panic disorder. More studies are needed in this area before the available data can be confirmed. As a supplement to drug therapy, cognitive behavioural therapy is effective. It is well tolerated, and may be beneficial in certain clinical situations. Its main drawback is the time commitment and effort needed to be made by the patient.

Differences in thyroid function studies in acutely manic adolescents with and without attention deficity hyperactivity disorder (ADHD).

The purpose of this study was to compare basal thyroid indices in adolescent (ages 12 to 18) bipolar patients with and without attention deficit hyperactivity disorder (ADHD). On the basis of earlier studies, the authors hypothesized that bipolar patients with comorbid ADHD would have lower serum triiodothyronine (T3) and thyroxine (T4) concentrations and higher serum thyroid stimulating hormone (TSH) concentrations compared with patients with bipolar disorder alone. Thirty adolescents who met DSM-III-R criteria for bipolar disorder and were hospitalized for the treatment of acute mania were assessed. Twenty patients (66%) had comorbid ADHD. The mean serum T4 concentration in this group was significantly lower than it was for patients with bipolar disorder alone. There were no significant differences between groups in serum T3 or TSH concentrations. Although, these data are preliminary and require further investigation, this may have important implications regarding the potential benefits of thyroid supplementation in adolescents with bipolar disorder and comorbid ADHD who do not respond to mood stabilizers alone.