Pharmacologic evidence for specificity of pursuit dysfunction to schizophrenia. Lithium carbonate associated with abnormal pursuit.

Conflicting findings regarding the prevalence of abnormal smooth-pursuit eye movements in patients with major affective disorders call into question the specificity of impaired smooth-pursuit eye movements to schizophrenia. We report that pursuit is impaired in 88% of lithium carbonate-treated affective disorder patients whose pursuit was normal prior to receiving this drug. Over half of lithium carbonate-treated affective disorder patients in remission also showed impairment of smooth-pursuit eye movements. In conjunction with recent prevalence data on family members of psychiatric patients, the findings support the specificity of abnormal pursuit as a biological trait associated with schizophrenia, but not with the major affective disorders. The mechanisms by which lithium carbonate impairs pursuit are discussed.

Efficacy of olanzapine in acute bipolar mania: a double-blind, placebo-controlled study. The Olanzipine HGGW Study Group.

BACKGROUND: We compared the efficacy and safety of olanzapine vs placebo for the treatment of acute bipolar mania. METHODS: Four-week, randomized, double-blind, parallel study. A total of 115 patients with a DSM-IV diagnosis of bipolar disorder, manic or mixed, were randomized to olanzapine, 5 to 20 mg/d (n = 55), or placebo (n = 60). The primary efficacy measure was the Young-Mania Rating Scale (Y-MRS) total score. Response and euthymia were defined, a priori, as at least a 50% improvement from baseline to end point and as a score of no less than 12 at end point in the Y-MRS total score, respectively. Safety was assessed using adverse events, Extrapyramidal Symptom (EPS) rating scales, laboratory values, electrocardiograms, vital signs, and weight change. RESULTS: Olanzapine-treated patients demonstrated a statistically significant greater mean (+/- SD) improvement in Y-MRS total score than placebo-treated patients (-14.8 +/- 12.5 and -8.1 +/- 12.7, respectively; P<.001), which was evident at the first postbaseline observation 1 week after randomization and was maintained throughout the study (last observation carried forward). Olanzapine-treated patients demonstrated a higher rate of response (65% vs 43%, respectively; P =.02) and euthymia (61% vs 36%, respectively; P =. 01) than placebo-treated patients. There were no statistically significant differences in EPSs between groups. However, olanzapine-treated patients had a statistically significant greater mean (+/- SD) weight gain than placebo-treated patients (2.1 +/- 2.8 vs 0.45 +/- 2.3 kg, respectively) and also experienced more treatment-emergent somnolence (21 patients [38.2%] vs 5 [8.3% ], respectively). CONCLUSION: Olanzapine demonstrated greater efficacy than placebo in the treatment of acute bipolar mania and was generally well tolerated.

A longitudinal study of plasma cortisol and depressive symptomatology by random regression analysis.

The authors utilized a random regression model to test the longitudinal relationship between depressive symptomatology and plasma cortisol levels obtained before and after the administration of dexamethasone in 62 affectively ill inpatients. This statistical model for longitudinal studies permits the inclusion of subjects with incomplete data as well as subjects measured at different time points. The most significant relationships were found between decreases in depressive symptoms and decreases in the 8:30 AM predexamethasone and the 4:00 PM postdexamethasone cortisol values. Patients were also classified as responders or nonresponders, and the rate of change in several plasma cortisol measures were separately analyzed for these two groups. No differences in the rate of change in plasma cortisol levels were found between responders and nonresponders. These results suggest that the decreases in cortisol production associated with clinical improvement may be partially explained by a regression toward the mean effect. Some of the possible explanations for these results are discussed.

Protein kinase C in platelets of depressed patients.

BACKGROUND: We studied the role of protein kinase C (PKC), a major regulatory enzyme and an important component of the phosphoinositide signaling system, in depression. METHODS: PKC was determined using [3H]phorbol dibutyrate (PDBu) as the radioligand in the membranal and cytosolic fractions of platelets obtained from hospitalized drug-free depressed patients during a baseline period and from drug-free normal control subjects. RESULTS: We observed that the [3H]PDBu binding was significantly higher in the cytosolic fraction obtained from platelets of depressed patients compared to normal control subjects. CONCLUSIONS: Our studies indicate increased formation of PKC in platelets of depressed patients. The significance and mechanisms involved in increased PKC in the cytosolic fraction of platelets are unclear, but they suggest that increased PKC may be associated with the pathophysiology of depressive illness.

Platelet serotonin-2 receptor binding sites in depression and suicide.

In order to examine the role of serotonin-2 (5HT2) receptors in depression and suicide, we determined 5HT2 receptors using 125I-lysergic acid diethylamide (LSD) as the binding ligand in platelets obtained from 20 normal control and 23 drug-free depressed patients. Our results indicate significantly increased 125I-LSD binding sites (Bmax) in the platelets of depressed patients compared with normal control subjects. We also observed that a subgroup of depressed patients with a recent history of suicide attempts or suicidal ideation had significantly higher 5HT2 binding sites as compared with nonsuicidal depressed patients and normal controls. There were no significant differences in the apparent dissociation constant (Kd) values in the platelets of depressed patients compared with normal control subjects. To examine if the baseline 5HT2 receptors are related to either the severity of illness or treatment response, we determined the relationships of the baseline Bmax and Kd with baseline Hamilton Depression Rating Scale (HDRS) and Brief Psychiatric Rating Scale (BPRS) scores and change in scores after treatment. We found no significant correlation between baseline Bmax and Kd with the baseline HDRS or BPRS scores or change in these scores after psychoactive drug treatment. These results thus indicate increased platelet 5HT2 receptors in depression, but much more so in depressed patients with suicidal ideation or attempts.

Behavioral and biochemical effects of methylphenidate in schizophrenic and nonschizophrenic patients.

The authors examined the specific behavioral and biochemical effects of intravenous methylphenidate in a sample of schizophrenic and nonschizophrenic patients. Twenty drug-free patients participated in a double-blind, placebo randomized study of methylphenidate, with multiple samples of plasma homovanillic acid (HVA) and serum growth hormone (GH) obtained during the infusion procedure. Methylphenidate caused a significant increase in positive symptoms that was relatively specific to the schizophrenic patients and was evident even in those with otherwise dormant symptomatology. When behavioral response was correlated with the biochemical responses (i.e., changes in plasma HVA and GH), there was a significant positive relationship between the increase in the BPRS-positive symptoms as well as the hostility/suspiciousness factor, and the increase in GH. These results suggest that the expression of psychotic symptoms may be associated with increased dopaminergic postsynaptic sensitivity, although the nonspecific nature of methylphenidate's actions discourages a stronger interpretation of the results.

The Clinician-Administered Rating Scale for Mania (CARS-M): development, reliability, and validity.

There are currently seven rating scales available to assess manic symptomatology. All, however, have some limitations that could restrict their clinical and research utility. To resolve these deficiencies the Clinician-Administered Rating Scale for Mania (CARS-M) was developed and normed on 96 patients with mixed diagnoses during baseline and following treatment. Interrater reliability was established across multiple raters viewing 14 videotaped interviews and comparing agreement among individual items and total scores. Test-retest reliability was assessed on 36 patients twice during baseline. The mean intraclass correlation coefficient among five raters across items for each of the 14 patients was 0.81, and for total scores 0.93. Principal components analysis of items revealed two factors: mania, and psychosis. Test-retest reliability was significant for both factors (range = 0.78 to 0.95). Internal validity, comparing each item with its respective total factor score, revealed significant correlations for all items. Correlation of CARS-M total scores with mania rating scale (MRS) total scores was 0.94. Results indicate the CARS-M is both a reliable and valid measure of the severity of manic symptomatology, which incorporates a number of methodological improvements leading to greater precision and clinical utility.

Pretreatment plasma homovanillic acid in schizophrenia and schizoaffective disorder: the influence of demographic variables and the inpatient drug-free period.

BACKGROUND: The relationship between plasma homovanillic acid (pHVA) and schizophrenic symptoms has not been conclusively determined. We reexamine pHVA levels in a new sample of patients with emphasis on demographic variables and the drug-free period. METHODS: Plasma HVA levels were studied in 54 schizophrenic and schizoaffective-disordered, drug-free inpatients suffering from a psychotic exacerbation. RESULTS: A significant correlation was observed between pHVA levels and the number of inpatient drug-free days in the total sample, as well as the schizophrenic patient subsample. Further, pHVA was significantly and positively correlated with the duration of illness in the schizophrenic patient subsample. Plasma HVA correlations with behavior, as measured by Brief Psychiatric Rating Scale factors (anxiety/depression and hostility/suspiciousness), emerged only when considering schizophrenic patients drug-free for more than 2 weeks. No correlation was found between pHVA and the age of illness onset or the duration of the delay of treatment of the first psychotic episode. CONCLUSIONS: The effects of antipsychotic withdrawal on levels of pHVA in clinical populations may have to be examined and controlled for in future studies attempting to study the relationship between this metabolite and behavior in acutely ill, drug-free schizophrenic patients.

Homovanillic acid in the cerebrospinal fluid: patterns of response after four weeks of neuroleptic treatment.

Lumbar cerebrospinal fluid (CSF) homovanillic acid (HVA) concentrations were measured before and after 4 weeks of neuroleptic treatment in schizophrenic (n = 15) and schizoaffective (n = 4) patients. Neuroleptic treatment induced a nonsignificant (17%) increase in CSF HVA group mean levels. For the total group, no correlations were found between pretreatment CSF HVA and clinical measures, or between changes in HVA and clinical response. An alternative interpretation was attempted by defining "tolerant" and "nontolerant" subgroups. A "tolerant" response was defined as a reduction in posttreatment HVA values below pretreatment levels, whereas a "nontolerant" response was characterized by posttreatment values above pretreatment levels. When thus defined, nontolerant patients had a significantly inferior clinical response to neuroleptics, in contrast to their tolerant counterparts. Further, although there was no difference in pretreatment CSF HVA values between these two groups, pretreatment clinical profiles did differ significantly. Also, in a retrospective analysis, nontolerant patients were found to have a significantly earlier age of illness onset, a greater number of prior psychiatric hospitalizations, and more time spent in psychiatric hospitals.

The effect of diagnosis and age on the DST: a metaanalytic approach.

The authors present new data on the results of the pretreatment Dexamethasone Suppression Test (DST) in 164 drug-free inpatients, as well as on the effects of age on postdexamethasone cortisol values. Nonsuppression rates were 18% in schizophrenic patients (n = 44), versus 46% in patients with a major depression (n = 56). In addition, a significant correlation was found between age and the 4:00 PM postdexamethasone cortisol value among the depressed patients (r = 0.33). The authors then applied a metaanalysis to summarize 25 other studies that have addressed the schizophrenia/major depression dichotomy as it relates to the DST outcome. Nonsuppression rates were consistently different in schizophrenic patients (19%) when compared to patients with a major depression (51%) or normal controls (7%). These differences were highly significant as measured by the Mantel-Haenszel chi-square statistic. A metaanalysis applied to a series of correlations obtained from 14 other studies reporting an age/postdexamethasone cortisol relationship in affective patients indicated a modest, but significant correlation (r = 0.24) in a total of 1284 patients (p less than 1 x 10(-8)).

CSF neurotensin concentrations and antipsychotic treatment in schizophrenia and schizoaffective disorder.

OBJECTIVE: The relationship between CSF neurotensin concentrations and measures of psychopathology in patients with schizophrenia or schizoaffective disorder was examined before and after treatment with antipsychotic drugs. METHOD: CSF neurotensin concentrations were measured in 42 drug-free patients with schizophrenia or schizoaffective disorder. For 18 of these patients, CSF neurotensin was measure again after 4 weeks of antipsychotic treatment. RESULTS: Significantly higher levels of pretreatment psychopathology were observed in the patients with the lowest CSF neurotensin concentrations. Furthermore, improvements in overall psychopathology and, particularly, negative symptoms were correlated with increases in CSF neurotensin concentrations during treatment. CONCLUSIONS: These findings provide further evidence for a role of neurotensin the pathophysiology of psychosis and in the mechanism of action of antipsychotic drugs.

Verapamil for the treatment of acute mania: a double-blind, placebo-controlled trial.

OBJECTIVE: This study investigated the efficacy of verapamil in acute mania. METHOD: The study was a 3-week double-blind, random-assignment, parallel-group, placebo-controlled inpatient trial of verapamil for patients with acute mania. Of the 32 study patients, 15 were given placebo and 17 were given verapamil. RESULTS: Mean absolute change scores on the Mania Rating Scale at endpoint, with baseline scores as the covariates, did not differ between the verapamil and placebo groups. There were no significant differences between the two groups in age, sex, and presence of psychosis. CONCLUSIONS: The investigators found no benefit of verapamil over placebo in treating acute mania.

Response of psychotic and nonpsychotic depression to phenelzine.

The authors studied 52 depressed inpatients to examine treatment response to phenelzine, a monoamine oxidase (MAO) inhibitor. All patients were classified into one of three RDC categories (definitely psychotic, probably psychotic, and nonpsychotic). For the entire sample, the mean platelet MAO inhibition level achieved with phenelzine was greater than 80%. Response to treatment was determined by independent clinical assessment and by the change in rating scores from baseline; 68% of the nonpsychotic, 43% of the probably psychotic, and 21% of the definitely psychotic patients were classified as responders. This differential response rate is similar to that reported in the literature for tricyclic antidepressants.

Efficacy of ECT: a meta-analysis.

The authors analyzed several rigorously controlled studies that compared the efficacy of ECT with that of simulated ECT, placebo, and antidepressants. The data from these studies were combined statistically (with the Mantel-Haenszel method for the combination of fourfold tables), showing ECT's clear superiority over all these other forms of treatment for severe depression. The authors similarly analyzed the data from several studies comparing the efficacy of unilateral nondominant ECT with that of bilateral ECT and found no significant difference in their efficacy.

Failure of urinary MHPG levels to predict treatment response in patients with unipolar depression.

The authors studied 64 depressed patients who were receiving a vanillylmandelic acid (VMA)-free diet and underwent a washout period (mean, 24 days) before treatment. During the washout period, a mean of 2.5 multiple 24-hour urinary 3-methoxy-4-hydroxyphenylglycol (MHPG) samples per patient were collected. Thirty-four patients were then treated with a "noradrenergic" antidepressant only (e.g., imipramine), and seven were treated with a "serotonergic" antidepressant only (e.g., amitriptyline). Twelve patients received combined drug treatment and 11 others spontaneously remitted. Response to treatment was rated on a clinical global evaluation scale from 1 (little or no response) to 7 (maximum response). No relationship was found between response to treatment, type of treatment, and the average pretreatment 24-hour urinary MHPG level. The authors thus failed to confirm the hypothesis that a low MHPG level predicts response to antidepressant treatment.

Elevation of CSF somatostatin concentrations in mania.

OBJECTIVE: The aim of this study was to compare levels of CSF somatostatin (somatotropin release-inhibiting factor) in drug-free patients with different major psychiatric disorders. METHOD: CSF somatostatin concentrations were measured in 66 drug-free inpatients with Research Diagnostic Criteria diagnoses of schizophrenia, major depressive disorder, manic disorder, or schizoaffective disorder. RESULTS: In comparison with both the patients with schizophrenia and the patients with schizoaffective disorder, the manic patients had markedly elevated CSF somatostatin concentrations. The depressed patients had significantly higher levels than the schizophrenic patients. CONCLUSIONS: Mania is associated with relatively higher CSF somatostatin concentrations.

Platelet MAO inhibition, urinary MHPG, and leukocyte beta-adrenergic receptors in depressed patients treated with phenelzine.

The authors investigated three biochemical indices of peripheral catecholamine activity in 36 depressed inpatients treated with the monoamine oxidase (MAO) inhibitor phenelzine. Platelet MAO activity, urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG), and leukocyte beta-adrenergic receptor functions were measured before and during the 4th week of phenelzine treatment. There were significant reductions in platelet MAO activity, urinary MHPG excretion, and depressive symptoms in all of the patients. Responders had the same decrease in MHPG as nonresponders. There were no changes in leukocyte beta-receptor function in a small subgroup of the patients.

Platelet serotonin-2A receptors: a potential biological marker for suicidal behavior.

OBJECTIVE: Abnormalities in the serotonergic system have been implicated in suicidal behavior. Higher numbers of serotonin-2 (5-HT2) receptors have been reported in the post-mortem brain of suicide victims. In order to further examine the role of 5-HT2A receptors in suicidal behavior, the authors studied 5-HT2A receptors in platelets of suicidal and nonsuicidal patients as well as normal comparison subjects. METHOD: 5-HT2A receptor levels were determined by using [125I]LSD as a radioligand in platelets obtained from hospitalized psychiatric patients (N = 131) and nonhospitalized normal comparison subjects (N = 40) during a drug-free baseline period. Patients were diagnosed according to DSM-III-R criteria, and suicidal behavior was identified by using the Hamilton Depression Rating Scale. RESULTS: The mean maximum number of binding sites (Bmax) of platelet 5-HT2A receptors for all suicidal patients was significantly higher than for nonsuicidal patients or normal comparison subjects. This significant difference remained when subgroups of suicidal patients with depression, schizophrenia, schizoaffective disorder, or bipolar illness were compared to the other two subject groups. The higher number of platelet 5-HT2A receptors in suicidal patients was independent of diagnosis. While there was no significant difference in Bmax between patients with serious suicidal ideation and those who made suicidal attempts, both groups had significantly higher Bmax than normal comparison subjects. CONCLUSIONS: The observed higher number of platelet 5-HT2A receptors in suicidal patients is independent of diagnosis and appears to be associated with both the brain and the platelets of suicidal patients. These results thus suggest the potential usefulness of platelet 5-HT2A receptors as a biological marker for identifying suicide-prone patients.

Relation of serum valproate concentration to response in mania.

OBJECTIVE: This study was designed to determine the relation of valproate serum levels to clinical improvement and development of adverse effects in hospitalized patients with acute mania. The initial fixed-dose escalation design, the monotherapy with divalproex, and the control of variables that is possible only with hospitalized patients reduced the confounding factors present in most outpatient studies of serum level-response relationships. METHOD: Sixty-five hospitalized patients who met the Research Diagnostic Criteria for bipolar disorder with mania were treated with divalproex, 750 mg/day for 2 days and then 1,000 mg/day on days 3-5; the dosage was subsequently adjusted as clinically indicated for the remainder of the 21-day study. Manic symptoms were assessed with the Mania Rating Scale, which is derived from the Schedule for Affective Disorders and Schizophrenia. RESULTS: At day 5, patients with serum valproate levels > or = 45 micrograms/ml were two to seven times as likely as patients with levels < 45 micrograms/ml to show 20% or greater improvement in scores on the manic syndrome subscale, the behavior and ideation subscale, elevated mood, increased activity, motor hyperactivity, and psychosis. Endpoint analyses yielded similar results. Adverse experiences characteristic of divalproex treatment were disproportionately associated with serum levels > or = 125 micrograms/ml. CONCLUSIONS: Acutely manic patients treated with divalproex who have valproate serum levels between 45 and 100-125 micrograms/ml are much more likely to have efficacious and well-tolerated responses than patients with lower or higher levels of valproate.

The relevance of clinical pharmacokinetics and therapeutic drug monitoring: anticonvulsant mood stabilizers and antipsychotics.

This review considers the relevance of clinical pharmacokinetics and the role of therapeutic drug monitoring (TDM) for two classes of psychotropics: the anticonvulsant mood stabilizers and the antipsychotics. In the first class, carbamazepine is a potent stimulator of the hepatic microsomal enzyme oxidation system, while valproic acid inhibits these same enzymes. In addition, these agents' highly protein-bound status can alter the availability of the free fraction of other coadministered agents. For both reasons, TDM during their administration may be useful. The antipsychotics demonstrate wide variations in absorption, first-pass effect, and volume of distribution among individuals. Depot antipsychotics have long elimination half-lives, often taking months to achieve steady-state levels or, conversely, to complete their washout. While correlations between antipsychotic plasma concentrations and clinical response are still under study, there are specific instances when TDM can be used to maximize clinical benefit and/or avoid adverse events.