Composite International Diagnostic Interview screening scales for DSM-IV anxiety and mood disorders.

BACKGROUND: Lack of coordination between screening studies for common mental disorders in primary care and community epidemiological samples impedes progress in clinical epidemiology. Short screening scales based on the World Health Organization (WHO) Composite International Diagnostic Interview (CIDI), the diagnostic interview used in community epidemiological surveys throughout the world, were developed to address this problem. METHOD: Expert reviews and cognitive interviews generated CIDI screening scale (CIDI-SC) item pools for 30-day DSM-IV-TR major depressive episode (MDE), generalized anxiety disorder (GAD), panic disorder (PD) and bipolar disorder (BPD). These items were administered to 3058 unselected patients in 29 US primary care offices. Blinded SCID clinical reinterviews were administered to 206 of these patients, oversampling screened positives. RESULTS: Stepwise regression selected optimal screening items to predict clinical diagnoses. Excellent concordance [area under the receiver operating characteristic curve (AUC)] was found between continuous CIDI-SC and DSM-IV/SCID diagnoses of 30-day MDE (0.93), GAD (0.88), PD (0.90) and BPD (0.97), with only 9-38 questions needed to administer all scales. CIDI-SC versus SCID prevalence differences are insignificant at the optimal CIDI-SC diagnostic thresholds (χ2 1 = 0.0-2.9, p = 0.09-0.94). Individual-level diagnostic concordance at these thresholds is substantial (AUC 0.81-0.86, sensitivity 68.0-80.2%, specificity 90.1-98.8%). Likelihood ratio positive (LR+) exceeds 10 and LR- is 0.1 or less at informative thresholds for all diagnoses. CONCLUSIONS: CIDI-SC operating characteristics are equivalent (MDE, GAD) or superior (PD, BPD) to those of the best alternative screening scales. CIDI-SC results can be compared directly to general population CIDI survey results or used to target and streamline second-stage CIDIs.

Aripiprazole monotherapy in the treatment of acute bipolar I mania: a randomized, double-blind, placebo- and lithium-controlled study.

OBJECTIVES: To evaluate the efficacy and safety of aripiprazole as acute and maintenance of effect monotherapy for acute bipolar mania. METHODS: Patients with acute bipolar I mania (DSM-IV-TR: YMRS > or =20), manic or mixed (with or without psychotic features) were randomized to double-blind aripiprazole (15-30 mg/day; n=155), placebo (n=165) or lithium (900-1500 mg/day; n=160) (1:1:1) for 3 weeks. Aripiprazole- and lithium-treated patients remained on blinded treatment for 9 additional weeks. The primary outcome was the mean change from baseline in YMRS Total score (LOCF) to Week 3. Secondary outcomes included the mean change from baseline in YMRS Total score (LOCF) at all other timepoints up to Week 12. RESULTS: Aripiprazole demonstrated significantly greater improvement than placebo in mean YMRS Total score from baseline to Day 2 (-4.3 vs.-2.8; p=0.003), and up to Week 3 (-12.6 vs. -9.0; p<0.001). Significant improvement in YMRS Total score was also seen with lithium versus placebo at Week 3 (-12.0 vs. -9.0; p=0.005). Improvements in YMRS Total score were maintained to Week 12 for aripiprazole (-14.5) and lithium (-12.7). Response rates at Week 3 were significantly higher with aripiprazole (46.8%) and lithium (45.8%) than placebo (34.4%; both p<0.05, LOCF); increasing to Week 12 with aripiprazole (56.5%) and lithium (49.0%). Most common adverse events with aripiprazole were headache, nausea, akathisia, sedation, and constipation; with lithium were nausea, headache, constipation, and tremor. CONCLUSIONS: Aripiprazole provided statistically significant improvement of acute mania within 2 days, continuing over 3 weeks and sustained over 12 weeks. The magnitude of improvement to Week 12 was similar with aripiprazole and lithium.

Failure of glucagon-like peptide-1 to induce panic attacks or anxiety in patients with panic disorder.

The insulin secretogogue glucagon like peptide-1 (GLP-1), as well as agents which enhance GLP-1 signaling, are being studied as potential treatments for diabetes. Pre-clinical evidence suggests that these agents may have neuropsychiatric side effects; however, there have been no investigations or reports of these effects in humans. We evaluated possible anxiogenic and panicogenic properties of GLP-1 in 9 healthy subjects (age 47+/-8 years) and 7 patients with panic disorder (age 38+/-17 years) using a single-blinded intravenous GLP-1 challenge (2pmol/kg/min over 60min). We assessed the occurrence of panic attacks during and after GLP-1 infusion and the emergence of anxiety or panic symptoms using the Acute Panic Inventory (API). No patient or healthy subject experienced any panic attacks at any point during this study. Moreover, there were no significant changes in API scores following the infusion in either group. These data suggest that in humans, intraveneously administered GLP-1 does not appear to have anxiogenic or panicogenic properties, even in patients at highest risk for such reactions.

Comparison of obese men and women with binge eating disorder seeking weight management.

OBJECTIVE: This study examined whether obese males with binge eating disorder (BED) seeking weight loss treatment differed significantly from obese females with BED seeking weight loss treatment in developmental variables, weight loss history, current and lifetime prevalence of psychiatric disorders, and metabolic abnormalities. METHODS: Psychiatric (using the Structural Clinical Interview for DSM-IV), medical, and laboratory assessments of 44 obese males with BED were compared with assessments from 44 age- and race-matched obese females with BED seeking weight loss treatment. RESULTS: High rates of mood disorders, anxiety disorders, and metabolic syndrome were observed in the population as a whole. Obese males with BED had attempted significantly fewer diets, medications and supplements for weight loss before seeking weight loss treatment. The two genders did not differ significantly in any other of the examined variables. CONCLUSIONS: Our results suggest that while obese men and women with BED who present for weight management are very similar, males had fewer previous attempts at weight loss, possibly related to their less pronounced body dissatisfaction or fewer help-seeking behaviors as compared to females. Our results also support findings of substantial comorbidity among obesity, BED, mood and anxiety disorders, and metabolic syndrome in weight loss seeking populations, in men as well as women.

Risk factors for neuroleptic malignant syndrome. A case-control study.

A number of risk factors have been proposed for the development of neuroleptic malignant syndrome, but these have not been subjected to controlled study. To address this problem, we performed a case-control study comparing 18 patients with neuroleptic malignant syndrome and 36 matched neuroleptic-treated control patients with no known history of the syndrome to identify potential risk factors. Patients with neuroleptic malignant syndrome displayed significantly greater psychomotor agitation, received significantly higher doses of neuroleptics at greater rates of dosage increase, and received a greater number of intramuscular injections than controls.

Valproate in the treatment of acute mania. A placebo-controlled study.

We conducted a placebo-controlled, double-blind study of valproate, a drug originally developed as an antiepileptic, in 36 patients with acute manic episodes who had previously failed to respond to or to tolerate lithium carbonate. Treatment duration was 7 to 21 days, with no other psychotropic medications permitted except lorazepam up to 4 mg/d during the first 10 days of treatment. Serum valproate concentrations were measured three times weekly; an unblinded investigator then adjusted dosage to produce serum concentrations between 50 and 100 mg/L. Valproate proved superior to placebo in alleviating manic symptoms. The 17 patients randomized to active drug demonstrated a median 54% decrease in scores on the Young Mania Rating Scale as compared with a median 5.0% decrease among the 19 patients receiving placebo. On the 100-point Global Assessment Scale of overall psychiatric functioning, patients receiving valproate improved by a median of 20 points as compared with a zero-point change with placebo. Significant differences also emerged on the Brief Psychiatric Rating Scale and in the number of supplemental doses of lorazepam required by the patients in each group. Substantial antimanic effects appeared within 1 to 4 days of achieving therapeutic serum valproate concentrations. Adverse effects were infrequent, with no adverse effect appearing significantly more frequently with valproate than with placebo. We conclude that valproate represents a useful new drug for the treatment of manic patients.

Polysomnographic characteristics of young manic patients. Comparison with unipolar depressed patients and normal control subjects.

Although sleep disturbance is a prominent feature of mania, its polysomnographic (PSG) features have received little study. To investigate more systematically the PSG characteristics of sleep in mania, all-night PSG evaluations were performed for two to four consecutive nights in 19 young manic patients (age range, 18 to 36 years), 19 age-matched patients with major depression, and 19 age-matched normal control subjects. Manic and depressed patients displayed nearly identical profiles of PSG abnormalities compared with normal control subjects, including disturbed sleep continuity, increased percentage of stage 1 sleep, shortened rapid eye movement latency, and increased rapid eye movement density. These results are similar to those reported in previous studies of major depression, and they are consistent with the possibility that the sleep disturbance in mania and major depression is caused by the same mechanism.

Twelve-month outcome after a first hospitalization for affective psychosis.

BACKGROUND: We studied the 12-month course of illness after a first hospitalization for affective psychosis to identify potential outcome predictors in this rarely studied patient population. METHODS: For this study, 109 patients consecutively admitted for their first psychiatric hospitalization for treatment of affective psychosis were recruited. Diagnostic, symptomatic, and functional evaluations were obtained at the index hospitalization and at 2, 6, and 12 months after discharge to assess syndromic, symptomatic, and functional outcome predictors. Factors associated with outcome were identified by means of multivariate analyses. RESULTS: Fifty-six percent of the patients achieved syndromic recovery during the 12-month follow-up. Full treatment compliance was associated with more frequent and rapid syndromic recovery. Full compliance was more common in white patients and in patients without substance abuse. Only 35% of these patients achieved symptomatic recovery during this same 12-month interval, and, similarly, only 35% achieved functional recovery. Symptomatic recovery was delayed in patients with substance abuse and was associated with higher socioeconomic status. Higher socioeconomic status was also associated with functional recovery, as was good premorbid function. CONCLUSIONS: Few patients achieved a favorable outcome in the year after a first hospitalization for an affective psychosis. Low socioeconomic status, poor premorbid function, treatment noncompliance, and substance abuse were associated with lower rates or delayed onset of recovery.

A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Divalproex Maintenance Study Group.

BACKGROUND: Long-term outcomes are often poor in patients with bipolar disorder despite treatment; more effective treatments are needed to reduce recurrences and morbidity. This study compared the efficacy of divalproex, lithium, and placebo as prophylactic therapy. METHODS: A randomized, double-blind, parallel-group multicenter study of treatment outcomes was conducted over a 52-week maintenance period. Patients who met the recovery criteria within 3 months of the onset of an index manic episode (n = 372) were randomized to maintenance treatment with divalproex, lithium, or placebo in a 2:1:1 ratio. Psychotropic medications were discontinued before randomization, except for open-label divalproex or lithium, which were gradually tapered over the first 2 weeks of maintenance treatment. The primary outcome measure was time to recurrence of any mood episode. Secondary measures were time to a manic episode, time to a depressive episode, average change from baseline in Schedule for Affective Disorders and Schizophrenia-Change Version subscale scores for depression and mania, and Global Assessment of Function scores. RESULTS: The divalproex group did not differ significantly from the placebo group in time to any mood episode. Divalproex was superior to placebo in terms of lower rates of discontinuation for either a recurrent mood episode or depressive episode. Divalproex was superior to lithium in longer duration of successful prophylaxis in the study and less deterioration in depressive symptoms and Global Assessment Scale scores. CONCLUSIONS: The treatments did not differ significantly on time to recurrence of any mood episode during maintenance therapy. Patients treated with divalproex had better outcomes than those treated with placebo or lithium on several secondary outcome measures.

Pharmacologic agents for the treatment of acute bipolar mania.

The knowledge base regarding the medical treatment of acute bipolar mania is rapidly expanding. Information about agents with established antimanic properties is increasing, and more agents with putative antimanic properties are being identified. We first review the controlled studies supporting the efficacy of the established antimanic agents lithium, valproate, and carbamazepine and standard antipsychotics. We then review available research on two important classes of drugs that are emerging as potential treatments for acute mania: the novel antipsychotics, which include clozapine, olanzapine, quetiapine, risperidone, and ziprasidone, and the new antiepileptics, which include gabapentin, lamotrigine, oxcarbazepine, tiagabine, topiramate, and zonisamide. We conclude that although controlled data are accumulating to support the efficacy of several atypical antipsychotics in the treatment of acute bipolar mania, particularly olanzapine, ziprasidone, and risperidone, the novel antiepileptics need more extensive study before it can be concluded that any of them possess specific antimanic properties. We also conclude that as the medical options for acute bipolar mania expand, treatment guidelines must remain both evidence based and flexible, so that they represent cutting edge medical science yet can be tailored to the specific needs of individual patients.

Misattribution of eating and obsessive-compulsive disorder symptoms to repressed memories of childhood sexual or physical abuse.

We describe three women with eating or obsessive-compulsive disorders who were told on initial presentation for treatment that their symptoms were due to forgotten experiences of childhood abuse and that recalling these repressed memories was critical to their recovery. The two patients who attempted to uncover these memories in psychotherapy were unable to do so and deteriorated. All three patients responded to treatment with conventional psychopharmacologic agents, however. These cases suggest that insisting to patients that they have been abused when they do not think they have been may have deleterious consequences.

Prevalence and severity of akathisia in patients on clozapine.

The atypical antipsychotic clozapine is reported to have unique therapeutic effects and to produce minimal extrapyramidal side effects. However, in a blind survey, akathisia was observed to be similar in prevalence and severity in patients treated with clozapine and those receiving standard neuroleptic antipsychotic drugs. In addition, as with standard antipsychotic drugs, the presence of akathisia in patients receiving clozapine was associated with a worse overall clinical outcome. The results suggest that akathisia may be a common side effect of all antipsychotic drugs, that akathisia may be produced by a mechanism distinct from other locomotor effects of these medications, and that patients receiving clozapine, like patients receiving standard antipsychotic drugs, should be monitored for akathisia.

Porcine stress syndrome: an animal model for the neuroleptic malignant syndrome?

The porcine stress syndrome is a genetic disorder of swine which, like neuroleptic malignant syndrome, is characterized by hyperthermia, muscle rigidity, and autonomic dysfunction. We investigated the porcine stress syndrome as a possible animal model for neuroleptic malignant syndrome in two ways. First, we administered haloperidol and lithium carbonate, alone and in combination, to susceptible and resistant swine. Second, we attempted to prevent the syndrome by pretreating animals with bromocriptine. Porcine stress syndrome was induced in 2 of 3 susceptible and 1 of 3 resistant swine by combined treatment with lithium and haloperidol, but was not triggered by treatment with lithium or haloperidol alone. Pretreatment with bromocriptine conferred no protection against the syndrome.

Enhanced response to repeated d-amphetamine challenge: evidence for behavioral sensitization 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 an important model of neural plasticity and has also been proposed as a model for a variety of psychiatric syndromes; however, there are no published controlled studies of behavioral sensitization in human subjects. The authors report results from a double-blind, placebo-controlled study of repeated d-amphetamine challenges in a sample of normal human volunteers. Eleven consecutively recruited normal volunteers participated in this 4-day protocol. Each subject 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 eye-blink rates were measured hourly for 5 hours following drug administration. All four measures demonstrated significantly enhanced increases following the second amphetamine dose as compared to the first amphetamine dose and both placebo conditions. These findings suggest that behavioral sensitization is measurable in human subjects.

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.

Placebo effect in randomized, controlled studies of acute bipolar mania and depression.

Randomized, double-blind, placebo-controlled, parallel group clinical trials have been the standard methodology for establishing the efficacy of new treatments for patients with bipolar disorder in manic, mixed, or depressive episodes. We examine the placebo response rate in acute treatment trials of acute mania (and mixed states) and bipolar depression. Also addressed are potential variables associated with placebo response, strategies to minimize placebo response, the optimum duration of placebo-controlled acute treatment trials, possible alternatives to the use of placebo, and the ramifications of these issues with regard to the design of studies in children, adolescents, and older adults with bipolar disorder.

Placebo effect in randomized, controlled maintenance studies of patients with bipolar disorder.

The prevention of mood episodes is an important goal of the maintenance treatment of patients with bipolar disorder. The rate of relapse on placebo compared with that on active treatment is an important issue in the design of future clinical trials of maintenance treatment. We examine the range and time course of placebo relapse rates in studies of patients with bipolar I disorder. In addition, we address the potential variables associated with placebo response, strategies to minimize placebo response, the optimum duration of placebo-controlled maintenance trials, possible alternatives to placebo control groups, and the impact of these considerations in maintenance studies of children, adolescents, and older adults with bipolar disorder.

Clinical and pharmacologic risk factors for neuroleptic malignant syndrome: a case-control study.

BACKGROUND: Pharmacologic and clinical risk factors for neuroleptic malignant syndrome have been suggested. High neuroleptic dose, rapid dosage increase, and parenteral administration were identified as risk factors in a case-control study; however, there are limited data regarding potential clinical risk factors. METHODS: To examine potential clinical risk factors, we conducted a case-control study, comparing 12 cases to 24 controls, all treated with neuroleptics at our center. In addition to examining previously postulated pharmacologic risk factors, we also assessed for presence of psychomotor agitation, confusion, disorganization, and catatonia. RESULTS: Significant differences were found between cases and controls for psychomotor agitation, confusion, disorganization, catatonia, mean and maximum neuroleptic dose, parenteral neuroleptic injections, neuroleptic dose increase within 5 days of the episode, magnitude of neuroleptic dose increase from initial dose, and extrapyramidal signs. CONCLUSIONS: This study demonstrated that psychopathological features such as psychomotor agitation, confusion, disorganized behavior, and catatonia may be risk factors for the neuroleptic malignant syndrome, in addition to pharmacologic risk factors and extrapyramidal signs, including akathisia. In clinical practice, careful monitoring for prodromal signs of neuroleptic malignant syndrome is required during neuroleptic treatment of patients with psychomotor agitation, confusion, and/or disorganization, while in the presence of catatonia these drugs should be avoided.

Valproate treatment of panic disorder and lactate-induced panic attacks.

Several lines of evidence suggest that the anticonvulsant drug valproate may have antipanic properties: (1) It enhances gamma-aminobutyric acid activity in the brain; (2) it has anxiolytic effects in animal models of anxiety; and (3) it has been reported to be effective in panic disorder in several preliminary studies; however, valproate has not been studied in the prevention of lactate-induced panic attacks. Sixteen patients with panic disorder underwent a lactate infusion followed by a 28-day treatment period with valproate and subsequent rechallenge with lactate. Response was measured by change in panic attack frequency and Hamilton Anxiety Scale (HAS) scores and by the ability of valproate to block lactate-induced panic on rechallenge. Of the 14 patients completing the 28-day trial, 10 (71%) experienced a greater than 50% reduction in the weekly frequency of panic attacks. Six (43%) had complete remission. HAS scores dropped significantly from a baseline mean of 30.8 +/- 9.4 (SD) to 12.6 +/- 7 after 4 weeks of treatment. Valproate blocked reinduction of panic symptoms on lactate rechallenge in 10 (83%) of 12 patients who had initially experienced panic symptoms on initial infusion. The significant reduction in spontaneous panic attacks and the blockade of lactate-induced panic symptoms by valproate support earlier studies suggesting that the drug may be an effective treatment for panic disorder.

Good sleep, bad sleep: a meta-analysis of polysomnographic measures in insomnia, depression, and narcolepsy.

Primary insomnia, major depression, and narcolepsy are usually considered to be separate disorders, distinguished by different polysomnographic profiles. But do polysomnographic data provide adequate evidence to segregate the three disorders, or might they display fundamentally the same sleep disturbance, differing only in degree? To test the viability of these two alternate hypotheses, the authors performed a meta-analysis of controlled polysomnographic studies of these disorders. A summary measure of degree of sleep disturbance was constructed from five variables: wakefulness after sleep onset, percentage of stage 1 sleep, percentage of stage 3 + 4 sleep, rapid eye movement (REM) latency, and REM density. The results of available studies for each variable were combined using a weighted average of effect sizes. An overall "sleep disturbance index" was then calculated by combining the estimates for the five above listed variables. On both the individual measures and especially on the summary index, insomnia, depression, and narcolepsy were arrayed on a simple continuum of progressively more severe sleep disturbance--congruent with the clinical observation that these disorders display progressively more disturbed sleep. These findings suggest that sleep can be disturbed in only a limited number of ways: in evaluating sleep architecture, it may not be possible to elaborate much beyond a single axis of good-to-bad sleep. Thus, polysomnographic measures may not provide adequate evidence to classify insomnia, depression, and narcolepsy as separate entities.