Response and remission rates with adjunctive aripiprazole in patients with major depressive disorder who exhibit minimal or no improvement on antidepressant monotherapy.

BACKGROUND: The efficacy of adjunctive aripiprazole in patients with major depressive disorder (MDD) with no improvement after 8 weeks of prior antidepressant monotherapy has not been evaluated. METHODS: A post hoc analysis of three similarly designed, randomised, double-blind, placebo-controlled, phase III studies was conducted investigating the efficacy and safety of aripiprazole adjunctive to standard antidepressant treatment (ADT) in MDD patients with a prior inadequate response to one to three ADTs. Minimal improvement to antidepressant monotherapy was defined as a Clinical Global Impressions - Improvement (CGI-I) score of 3 and non-improvement as a CGI-I of 4 at weeks 6 and 8 of antidepressant monotherapy. RESULTS: The end-point response rate for ADT minimal improvers receiving adjunctive aripiprazole was 38.8% vs. 26.6% for adjunctive placebo (p < 0.05; number needed to treat [NNT] = 9 [95% confidence interval: 4.8-27.7]), and for ADT non-improvers receiving adjunctive aripiprazole was 24.0% vs. 10.3% for adjunctive placebo (p < 0.05; NNT = 8 [95% confidence interval: 4.4-21.5]). ADT minimal improvers and non-improvers demonstrated significant improvements in response vs. ADT alone as early as after 1 and 2 weeks of adjunctive treatment, respectively. The end-point remission rate for ADT minimal improvers receiving adjunctive aripiprazole was 34.2% vs. 21.0% for adjunctive placebo (p < 0.05; NNT = 8), and for ADT non-improvers receiving adjunctive aripiprazole was 16.0% vs. 5.9% for adjunctive placebo (p < 0.05; NNT = 10). The most common adverse events for ADT minimal improvers and non-improvers receiving adjunctive aripiprazole were akathisia, restlessness and insomnia. CONCLUSION: Patients with minimal or no improvement after 8 weeks of antidepressant monotherapy significantly benefited from adjunctive aripiprazole treatment, supporting the efficacy of this treatment for MDD patients with all levels of response to ADT.

Effect of des-tyrosine-gamma-endorphin in tardive dyskinesia.

The endorphin neuropeptides may have neuroleptic-like effects on dopamine function and may be antischizophrenic. Ten chronic psychotic patients with neuroleptic-induced tardive dyskinesia and parkinsonism received placebo and des-tyrosine-gamma-endorphin (DT gamma E). Drug effects on movement disorders and eye-blinking rates were assessed by blind evaluations of randomly sequenced videotapes made during standardized examinations before and 30, 60, and 120 minutes after each injection and at 24 hours postinjection on days of consecutive treatment. Changes in schizophrenic symptoms were evaluated openly with the schizophrenia subscale of the Comprehensive Psychiatric Rating Scale. There were no significant effects of DT gamma E on any parameter and no side effects. This suggests that DT gamma E, within the tested dose range, does not influence the pathophysiology of neuroleptic-induced dyskinesias or chronic schizophrenia or have neuroleptic properties. However, DT gamma E is well tolerated and should be tested with higher doses during prolonged treatment.

gamma-Acetylenic GABA in tardive dyskinesia.

Brain gamma-aminobutyric acid (GABA) has been proposed to play a role in the modulation of extrapyramidal motor function. The effects of increasing brain GABA with gamma-acetylenic GABA (GAG), a drug that inhibits GABA transaminase, were evaluated in ten patients with stable tardive dyskinesia during a blind placebo-controlled trial. Drug effects during active treatment and two placebo periods were evaluated by scoring randomly sequenced videotapes of tardive dyskinesia and parkinsonian symptoms recorded weekly during a standardized examination. Tardive dyskinesia was significantly reduced, and preexisting parkinsonism increased slightly. The largest decrease in tardive dyskinesia symptoms occurred in patients receiving higher neuroleptic doses, suggesting an interaction between GABA and dopamine. Prolactin values increased but growth hormone values were unchanged. Psychiatric symptoms were also unchanged during GAG treatment.

Tardive dyskinesia in the aged. Duration of treatment relationships.

Although tardive dyskinesia (TD) is recognized to result from neuroleptic drug exposure, data conflict about the importance of the quantity of that exposure in producing TD. The relationship between duration of neuroleptic treatment (one to 301 months) and TD was studied in 57 elderly psychiatric inpatients. Examinations for TD and parkinsonism were quantified on the Abnormal Involuntary Movement Scale (AIMS) and on a parkinsonism severity scale. Prevalence of presumed TD was 49% and of parkinsonism 51%. Prevalence of TD increased with longer treatment, but parkinsonism was independent of treatment duration. Linear multiple regression analysis showed that the AIMS score was correlated positively with treatment duration and negatively with parkinsonism. Logistic multiple regression analysis verified these relationships and was more successful at predicting TD. The length of neuroleptic treatment necessary to produce TD was calculated from the logistic model at 10.8 months (95% confidence interval, zero to 25.6 months). These analyses showed the greatest rise in risk of TD occurred within the first two years of drug therapy.

Initial anticholinergic prophylaxis for neuroleptic-induced extrapyramidal syndromes.

Initial prophylaxis with anticholinergics for neuroleptic-induced extrapyramidal syndromes (EPSs) is controversial. Recommendations, based on conflicting research findings, vary from routine prophylactic use of anticholinergics to withholding these agents until dystonia, akathisia, or parkinsonism develops. To determine whether anticholinergic prophylaxis influenced EPS rates during the first 21 days of neuroleptic treatment, 215 psychotic inpatients were reviewed. Initial prophylaxis with anticholinergic drugs significantly reduced the occurrence of EPSs. This treatment's efficacy depended on a complex interaction of variables, including the patient's sex and age, antipsychotic drug type and dose, and treatment phase.

The prevalence of tardive dyskinesia in neuroleptic-treated diabetics. A controlled study.

In a controlled study, we compared the prevalence of tardive dyskinesia in 38 neuroleptic-treated diabetics with the prevalence of tardive dyskinesia in a group of 38 nondiabetic neuroleptic-treated controls, matched for age, sex, psychiatric diagnosis, and dose and duration of neuroleptic treatment. Members of each group were evaluated for movement disorders by a rater who used standard rating scales and was "blind" to all diagnoses and treatments. Neuroleptic-treated diabetics had a significantly higher prevalence and severity of tardive dyskinesia. There were no differences between groups on other possible risk factors for tardive dyskinesia, including parkinsonism, anticholinergic drug treatment, or cognitive function. These data suggest that diabetes mellitus should be examined further as a risk factor for tardive dyskinesia.

The effect of tetrahydroisoxazolopyridinol (THIP) in tardive dyskinesia: a new gamma-aminobutyric acid agonist.

gamma-Aminobutyric acid (GABA) agonists have been proposed for the treatment of tardive dyskinesia, but their therapeutic potential has been limited by side effects and toxicity. To elucidate further the role of GABA in neuroleptic-induced dyskinesias, we evaluated tetrahydroisoxazolopyridinol (THIP), a new, less toxic GABA analog and GABA receptor agonist, in both a dose-finding (single-dose) pilot study with five patients and a longer (four-week) placebo-controlled study with 13 patients. The patients were videotaped during a standardized examination; tardive dyskinesia, parkinsonian symptoms, and eye-blinking rates were rated blindly and randomly. The maximal short-term dose of THIP was 10 to 25 mg, whereas in the longer-term study the highest daily dose ranged from 20 to 120 mg. Tardive dyskinesia was unchanged during THIP treatment, but preexisting parkinsonism increased significantly and eye-blinking rates decreased. Psychiatric symptoms showed no significant changes, although tension and depression lessened. Side effects included sedation, confusion, dizziness, vomiting, and myoclonic jerks. Although THIP is not an effective new treatment for tardive dyskinesia, more specific GABA agonists should be evaluated in future studies of this syndrome.

The prevalence of metoclopramide-induced tardive dyskinesia and acute extrapyramidal movement disorders.

BACKGROUND: Metoclopramide hydrochloride, a neuroleptic dopamine receptor antagonist used to treat gastric ailments, is reported to cause extrapyramidal movement disorders. The goals of this study were (1) to determine the prevalence and severity of tardive dyskinesia and acute extrapyramidal movement syndromes including akathisia, acute dystonia, and drug-induced parkinsonism in metoclopramide-treated patients and (2) to compare the prevalence and severity of tardive dyskinesia in metoclopramide-treated diabetics and nondiabetics. METHODS: From a list of metoclopramide-treated patients received from the Portland (Ore) Veterans Affairs Medical Center pharmacy, 53 patients met inclusion criteria and 51 (96%) agreed to participate. Controls consisted of a convenience sample drawn from the Portland Veterans Affairs Medical Center Outpatient Clinic who were matched to subjects on age (+/- 10 years), gender, and presence or absence of diabetes. Of 61 potential controls contacted, 51 (84%) agreed to participate. Metoclopramide-treated subjects and controls were seen by a rater who was "blind" to all diagnoses and treatments. The rater performed a standardized examination used to elicit signs and symptoms of tardive dyskinesia and acute extrapyramidal movement syndromes. RESULTS: The relative risk for tardive dyskinesia was 1.67 (95% confidence interval, 0.93 to 2.97), and the relative risk for drug-induced parkinsonism was 4.0 (95% confidence interval, 1.5 to 10.5). Metoclopramide-treated patients had significantly greater severity of tardive dyskinesia, drug-induced parkinsonism, and subjective akathisia than controls. Use of metoclopramide was associated with impairment in ambulation and increased use of benzodiazepines. Metoclopramide-treated diabetics had significantly greater severity of tardive dyskinesia than metoclopramide-treated nondiabetics. CONCLUSIONS: Metoclopramide use is associated with a significantly increased prevalence and severity of several extrapyramidal movement disorders.

Neuroleptic-induced parkinsonism in older schizophrenics.

The association of neuroleptic drug-induced parkinsonism (DIP) with factors related to brain structure and function are poorly understood. Twenty-one medicated schizophrenics over age 55 years were evaluated for parkinsonism, tardive dyskinesia, psychiatric symptoms, ventricular/brain ratio (VBR), and neuropsychological function. Sixteen (76%) of the patients had DIP, whereas 10 (48%) had tardive dyskinesia. Increased severity of parkinsonism was significantly associated with larger VBR and the severity of negative symptoms. Severity of parkinsonism predicted poor visual-spatial function, whereas negative symptoms were modestly predictive of impairment in both verbal ability and cognitive flexibility. These findings suggest that brain atrophy may be a risk factor for DIP. The pattern of cognitive dysfunction associated with DIP in this sample is similar to that found in idiopathic Parkinson's disease. Dopaminergic dysfunction may underlie the pattern of pathology described in this report.

Three-year follow-up of older schizophrenics: extrapyramidal syndromes, psychiatric symptoms, and ventricular brain ratio.

Longitudinal evaluation of psychiatric patients often yields information that cross-sectional study does not. We previously examined 31 older (age greater than 55) chronic schizophrenics for prevalence of extrapyramidal side effects, severity of psychiatric symptoms, and ventricular brain ratio (VBR). We reexamined 22 of these patients after 2-4 years. Tardive dyskinesia (TD) and drug-induced parkinsonism (DIP) were common (mean prevalences were 52% and 62%, respectively) and often occurred together (38%). The overall prevalences of the disorders did not change significantly with time, although there was some individual fluctuation in diagnosis. Severity of TD was constant, but severity of DIP decreased, probably because neuroleptic doses were significantly decreased. Magnitude of DIP was positively correlated with VBR and severity of negative symptoms of schizophrenia. The correlation of DIP and negative symptoms occurred primarily because of the similarity between masked facies and blunted affect. VBR did not change over the follow-up period. Negative symptoms of schizophrenia were prevalent, moderately severe, and quite stable over time in this cohort. Positive symptoms were less severe but highly variable between examinations.

Tardive dyskinesia in an adolescent.

The frequent use of neuroleptic drugs in the treatment of disturbed children and adolescents demands that clinicians be aware of the danger of tardive dyskinesia in this age group. A case history of a 15-year-old boy who developed incapacitating tardive dyskinesia that resolved during treatment with deanol is presented. The recognition, differential diagnosis, and management of this syndrome in children are discussed. Lithium carbonate was a useful alternative to neuroleptics in managing the adolescent's disturbed behavior.

Deanol in the treatment of tardive dyskinesia.

A patient who developed severe tardive dyskinesia after the termination of long-term phenothiazine therapy was successfully treated with deanol, a possible precursor of acetylcholine. Physiological measurements were obtained to quantify the clinical course. The authors discuss the practical and heuristic implications of these observations and suggest further consideration of therapy directed toward enhancement of cholinergic activity in the central nervous system.

Use of neuroleptic-induced extrapyramidal symptoms to predict future vulnerability to side effects.

OBJECTIVE: Susceptibility to neuroleptic-induced extrapyramidal syndromes varies widely, even within age and sex subgroups. Individual vulnerability to extrapyramidal syndromes has been assumed to explain this, but the utility of past history for predicting future occurrence of extrapyramidal syndromes has not been studied extensively. This investigation was undertaken to determine whether patients' previous histories of extrapyramidal syndromes predict future episodes of extrapyramidal syndromes and to compare the importance of this predictive factor with patient age, sex, neuroleptic dose, and anticholinergic dose as predictors of extrapyramidal syndromes. METHODS: The charts of 62 schizophrenic patients with multiple neuroleptic treatment episodes were reviewed. Extrapyramidal syndromes, neuroleptic drug doses, and anticholinergic drug doses during the first 21 days of each treatment episode were recorded. RESULTS: Previous extrapyramidal syndromes correctly predicted extrapyramidal syndromes in subsequent treatments for 84% of the patients. Variations in neuroleptic potency, neuroleptic dose, and anticholinergic dose partially explained incorrect predictions. CONCLUSIONS: These results support the hypothesis that patients with a history of extrapyramidal syndromes are at greater risk for future extrapyramidal syndromes. If confirmed, these results strongly support individual susceptibility as a major predictor of extrapyramidal syndromes and indicate that prophylaxis of extrapyramidal syndromes should be considered for patients who have previously suffered extrapyramidal syndromes from similarly prescribed neuroleptic therapy.

Ten-year outcome of tardive dyskinesia.

OBJECTIVE: The purpose of this study was to assess the long-term outcome of patients with tardive dyskinesia. METHOD: A group of 122 neuroleptic-treated Hungarian outpatients were assessed for tardive dyskinesia on the Abnormal Involuntary Movement Scale and the Tardive Dyskinesia Rating Scale by the same rater over a 10-year period. RESULTS: Sixty-three of the patients received both 5- and 10-year follow-up assessments and are the subjects of this report. The overall prevalence of tardive dyskinesia in this group changed little over time; it was 30.2% at baseline, 36.5% at 5 years, and 31.7% at 10 years. However, there were changes in the tardive dyskinesia status of individual patients; 11 patients had remissions, and 12 who did not have tardive dyskinesia at the baseline assessment had developed it by the 10-year assessment. These two subgroups did not differ significantly on demographic and drug history variables. Outcome of tardive dyskinesia was not significantly related to neuroleptic treatment or to age. CONCLUSIONS: The data of this 10-year follow-up study provide evidence for the long-term stability of tardive dyskinesia and for the feasibility of maintenance neuroleptic therapy for chronic psychotic patients who have tardive dyskinesia.

Pharmacology of blepharospasm-oromandibular dystonia syndrome.

Blepharospasm and oromandibular dystonia are clinically similar to other hyperkinetic movement disorders. Dopaminergic antagonist (neuroleptic) and purported cholinergic agonist (deanol) treatment improved symptoms, whereas dopaminergic agonist (carbidopa/levodopa) and cholinergic antagonist (benztropine) drugs worsened symptoms in two patients. This suggested that the syndrome is also pharmacologically related to the hyperkinetic dyskinesias. Symptoms worsened substantially during carbidopa/levodopa but temporarily resolved in one patient and improved in another when the drug was discontinued. This suggests that the pathophysiology of these symptoms involves an idiopathic form of receptor hypersensitivity that can be modified by agonist treatment. The effect of cholinergic agents was less than the effect of dopaminergic drugs, implying that dopamine plays a predominant role in the pathophysiology.

Coadministration of haloperidol and SCH-23390 prevents the increase in "perforated" synapses due to either drug alone.

Perforated synapses, which have a discontinuous density along the postsynaptic membrane, undergo changes in numbers under various experimental conditions. We have previously shown that 14-day administration of haloperidol, a typical neuroleptic which induces extrapyramidal side effects (EPS) and tardive dyskinesia (TD) in patients, causes an increase in the percentage of perforated synapses within the caudate nucleus. This increase was reversed if the animals were taken off the drug for an equal period of time (14 days). There was no effect within the nucleus accumbens. The atypical antipsychotic drug, clozapine, which when administered precipitates a very much lower incidence of EPS and TD, had no effect on the percentage of perforated synapses within either the caudate or nucleus accumbens. Because clozapine binds to both dopamine (DA) D1 and D2 receptors, it was of interest to determine if any changes in perforated synapses occurred following administration of the specific D1 antagonist, SCH-23390. Furthermore, because the action of D2 agonist may be dependent on the activation of the D1 receptor, we asked whether concomitant blockade of the D1 receptor could prevent the increase in perforated synapses due to the action of haloperidol, a drug which upregulates D2 receptors. We found that 14-day treatment with SCH-23390 (1.0 mg/kg per day) or haloperidol (0.5 mg/kg per day) caused an increase in the percentage of perforated synapses within the caudate but not the nucleus accumbens. There was a corresponding increase in DA D1 and D2 receptors in the caudate following administration of SCH-23390 or haloperidol, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Seven-year follow-up of tardive dyskinesia in Hungarian outpatients.

Of 122 Hungarian outpatients treated with neuroleptics, 79 (64.8%) were available for follow-up 7 years after their original assessment for tardive dyskinesia (TD). Ratings on the Abnormal Involuntary Movements Scale and the Simpson Dyskinesia Rating Scale increased significantly. The number of TD cases identified by research diagnostic criteria increased by only 9%: 12 of 28 patients no longer showed TD 7 years later, while 19 of 51 patients developed new TD.

Side effect profiles of new antipsychotic agents.

Although neuroleptic drugs have become the mainstay of treating acute and chronic psychosis, they are substantially limited by troublesome side effects. The traditional neuroleptic drugs have a wide array of central nervous system and peripheral system side effects that often lead to problems in management or patient noncompliance. Of particular difficulty are the extrapyramidal symptoms and tardive dyskinesia. However, other side effects of seizures, sedation, neuroleptic malignant syndrome and cardiovascular, hematologic, endocrinological, and weight gain problems remain as clinical management challenges posed by existing antipsychotic drug therapy. Considerable progress has been made in improving the motor side effect profile with the advent of clozapine and risperidone. However, each of these drugs has its own dose-limiting side effect profile. Two new drugs, olanzapine and sertindole, are now added to the pharmacopeia for treating psychosis. They further improve the benefit/ risk ratio because they have even fewer EPS and other side effects. Overall, these new antipsychotic agents greatly improve the treatment of psychosis by reducing drug-induced morbidity and improving the quality of life for patients.

Tardive dyskinesia: pathophysiology and animal models.

Tardive dyskinesia stimulated extensive research into the mechanisms of antipsychotic drug action. A wide range of homologous, analogous, and correlational animal models have been developed to explore how typical neuroleptic drugs do and atypical antipsychotic agents do not seem to cause tardive dyskinesia. The leading hypotheses of the underlying pathophysiology of tardive dyskinesia include dopamine receptor hypersensitivity, GABA insufficiency, and/or structural abnormalities. All these hypotheses have data both for and against them. The roles of psychosis and aging must also be considered in any explanation of tardive dyskinesia. The challenge still remains of how to accurately attribute the relative contributions of each of these factors to the pathogenesis and pathophysiology of tardive dyskinesia. Fortunately, the atypical antipsychotic agents appear to greatly decrease the liability of developing tardive dyskinesia, but how this occurs remains an open and fascinating line of inquiry.

The relationship of pharmacology to side effects.

Most traditional neuroleptics have a narrow therapeutic-to-toxic index, and thus, the novel antipsychotics are the result of a search to substantially widen the distance between the dose that treats psychosis and the one that produces adverse effects. In vitro binding profiles have been created for the atypical antipsychotics that have been approved by the U.S. Food and Drug Administration (FDA)-clozapine, olanzapine, and risperidone and those that are under FDA review-quetiapine and sertindole. These profiles, which were compared with that of the typical neuroleptic haloperidol, provide guidance for predicting the adverse effects produced by these drugs. Most conventional antipsychotics have central nervous system effects, particularly extrapyramidal symptoms (EPS) and tardive dyskinesia, sedation, and dulling of cognition. Other adverse effects of the typical antipsychotics include the neuroleptic malignant syndrome, orthostatic hypotension, changes in liver function, anticholinergic and antiadrenergic side effects, sexual dysfunction, and weight gain. The newer agents have a lower incidence of EPS and tardive dyskinesia, while weight gain and changes in blood pressure and liver function tests are adverse effects that have been associated with the use of the newer agents. The favorable side effect profile of these new antipsychotics is likely to make patients more willing to continue treatment, and thus these agents represent a step forward in the treatment of patients with severe, chronic mental illness.