Neuroleptic Discontinuation Research Articles

Neuroleptic low-dose long-term strategy and intermittent therapy strategy in chronic schizophrenia--a critical review

Much effort has been devoted during the past decade in finding new therapeutic approaches to cope with the commonly occurring adverse side effects of long-term neuroleptic maintenance treatment of schizophrenics, such as, in particular, akathisia, parkinsonian symptoms and tardive dyskinesia. Both low-dose maintenance (e.g. long-term treatment at dosages reduced to one-fifth or even less of conventional dosage levels in remitted and stable schizophrenics) and intermittent or-target medication strategies (e.g. discontinuation of neuroleptics in remitted stable chronic schizophrenics, aimed at resuming the medication as soon as prodromal signs of a relapse or actual relapses occur) might eventually imply for many schizophrenics a substantial reduction in total long-term neuroleptic dosages. This may lead to a reduction in the incidence of side effects and to an improvement in social integration. A critical review of the results published so far arrives at the following conclusions: 1. low-dose maintenance therapy is just as effective as a standard dose regimen and even superior to intermittent (target) medication. Especially if the dosage is increased in case of exacerbations; 2. these results are representative for a very small group of patients only, since the study populations were highly selective.

Nonneuroleptic treatment of disruptive behavior in organic mental syndromes.

To summarize the literature describing nonneuroleptic treatments of unacceptably disruptive behavior in chronically institutionalized psychiatric patients with mental retardation, autism, organic brain syndrome, and dementia. Relevant articles were identified from a MEDLINE search of the above diagnoses linked with "aggression" and "psychomotor agitation." Additional references were found in the bibliographies of these articles. The studies reviewed were limited to prospective evaluations of nonneuroleptic drug therapy of these behavior disturbances. Case reports, case series, and retrospective studies were excluded. Studies of patients with schizophrenia, affective disorders, and personality disorders were also excluded. Studies of lithium, beta-blockers, carbamazepine, benzodiazepines, and buspirone were adequate for review. As a rule, these studies are hampered by poor design. The lithium studies suggest that mentally retarded patients with behavior disturbances may respond to lithium treatment. The beta-blocker studies suggest improvement in patients with mental retardation, autism, organic brain syndrome, and dementia. Neuroleptic discontinuation or a decrease in dose was possible in some patients. The carbamazepine studies were inconclusive. Carbamazepine should be reserved for patients with concomitant seizure disorders. Benzodiazepines were helpful in treating elderly demented patients. Thus far, buspirone has been evaluated in only a few, poorly designed studies and is not yet recommended for treatment of behavior disturbances. Legislation has restricted the use of neuroleptics in many patients receiving long-term healthcare. Despite the questionable validity of the studies reviewed, lithium, beta-blockers, carbamazepine, and benzodiazepines may be considered as alternatives to neuroleptics in selected cases.

Neuroleptic discontinuation in the very stable schizophrenic patient: Relapse rates and serum neuroleptic levels

AbstractThis double‐blind, placebo‐controlled study investigated the effect of discontinuation of maintenance neuroleptic medication in chronic, long‐stay schizophrenic patients who had been clinically stable for over 5 years. After 12 months, 75 per cent of the patients on placebo had relapsed as compared to 33 per cent on active medication and relapses in the placebo group occurred significantly earlier during the study; survival analysis revealed the differences to be statistically significant. No clear predictors of relapse could be identified, although patients who relapsed from either group were more likely to have had higher scores for anxiety symptoms and a lower serum prolactin level at baseline. It was concluded that even in older patients who have been chronically ill with prominent negative symptoms and living in a relatively undemanding environment on stable doses of neuroleptics, the risk of relapse remains unacceptably high after abrupt withdrawal of maintenance neuroleptic therapy.

Clinical predictors of relapse following neuroleptic withdrawal

The validity of previously hypothesized predictors of elapse following neuroleptic discontinuation was examined. One hundred sixty-two outpatients, with either Research Diagnotic Criteria schizophrenia or schizoaffective disorder, were discontinued from neuroleptic medication for a 28-day period or until judged to be relapsed. Pre-discontinuation neuroleptic dosage level, the severity of psychotic symptoms, and the presence of dyskinetic movements prior to neuroleptic discontinuation were the predictor variables. Of the 162 patients, 62.7% did not relapse during the study period. There were no differences in the survival rates between the patients withdrawn from oral versus depot neuroleptics. Neuroleptic dosage, but not severity of psychotic symptoms or dyskinetic movements, predicted relapse. These results support the hypothesis that pre-withdrawal neuroleptic dosage level predicts relapse, but fail to validate either severity of psychotic symptoms or presence of dyskinetic movements as predictors of relapse.

Brief neuroleptic discontinuation and clinical symptoms in Kraepelinian and non-Kraepelinian chronic schizophrenic patients

Neuroleptic medication was abruptly discontinued in 24 male chronic schizophrenic patients who were subdivided on the basis of their history of illness into Kraepelinian ( n=8) and non-Kraepelinian ( n=16) subgroups. These patients were kept drug free for 6 weeks and then returned to treatment with haloperidol, 20 mg/day. Half of the non-Kraepelinian patients developed exacerbations of their symptoms, which quickly resolved when they were returned to medication, while none of the Kraepelinian patients showed a worsening of symptomatology. On- medication clinical severity failed to predict risk for exacerbation, with severity of exacerbation predicting the amount of improvement when returned to medication. The Kraepelinian patients were found to be much less variable than the non- Kraepelinian patients in their symptoms during both medication manipulations, suggesting that medication truly has a negligible effect on them.

Changes in plasma homovanillic acid concentrations in schizophrenic patients following neuroleptic discontinuation.

Changes in plasma levels of the dopamine metabolite homovanillic acid have been reported to correlate with changes in the severity of schizophrenic symptoms during neuroleptic administration and after neuroleptic discontinuation. This study examined the effects of discontinuation of neuroleptic treatment on plasma homovanillic acid levels in 23 patients with chronic schizophrenia. It was hypothesized that clinical decompensation would be associated with increased plasma homovanillic acid levels. Plasma homovanillic acid was measured during administration of neuroleptic medication and during a subsequent 6-week drug-free period. Nine patients decompensated during the drug-free period and 14 patients did not. Following drug discontinuation, plasma homovanillic acid concentrations were higher in schizophrenic patients who decompensated than in those who did not. Furthermore, peak plasma homovanillic acid elevation after discontinuation of neuroleptic medication was significantly correlated with peak Brief Psychiatric Rating Scale increase. The data suggest that, in some schizophrenic patients, symptomatic decompensation after discontinuation of neuroleptic treatment is associated with increases in dopamine turnover.

Pharmacological characterization of tardive akathisia

A patient with tardive neuroleptic-induced akathisia was investigated with multiple pharmacological challenges. It was noted that the patient responded positively to benztropine, bromocriptine, and propranolol, and negatively to physostigmine, and showed little or no response to discontinuation of neuroleptics and challenges with metoclopramide, metoprolol, atenoiol, and clonidine. The implications of this pharmacological characterization for the understanding of the pathophysiology of tardive akathisia in relation to acute akathisia and tardive dyskinesia are discussed.

Continuous versus targeted medication in schizophrenic outpatients: outcome results [published erratum appears in Am J Psychiatry 1991 Jun;148(6):819

The authors report on the outcome of treatment of 116 outpatients with chronic schizophrenia who were assigned to a 2-year, single-blind course of treatment with either targeted or continuous medication. These patients were not restricted to those who were good candidates for a medication reduction strategy. Continuous medication was superior to targeted medication in preventing decompensations and hospitalizations and in extent of employment at 2 years. Other measures of psychopathology and functioning at 1 and 2 years did not differentiate the two groups of patients. The targeted approach achieved a substantial reduction in total medication through a reduction in the number of days of medication administration.

Neuroleptic Malignant Syndrome in a Multiple Trauma Patient

Neuroleptic malignant syndrome is a little-known adverse reaction to neuroleptic administration characterized by hyperpyrexia, leukocytosis, creatine kinase elevations, muscular rigidity, autonomic dysfunction, and alterations in level of consciousness. Neuroleptic malignant syndrome has an associated 20% mortality but can be reversed when treated with neuroleptic discontinuation and administration of bromocriptine and dantrolene. Early diagnosis in the trauma unit may prevent an extensive workup for presumed sepsis. To our knowledge, neuroleptic malignant syndrome has not previously been reported in a multiple trauma patients.

Increments in plasma homovanillic acid concentrations after neuroleptic discontinuation are associated with worsening of schizophrenic symptoms

Khan, René s., Farooq Amin, Peter Powchik, Peter Knott, Marvin Goldstein, Seth Apter, Ben Kerman, Stacey Jaff and Michael Davidson: Increments in Plasma Homovanillic Acid Concentrations after Neuroleptic Discontinuation are Associated with Worsening of Schizophrenic Symptoms. Prog. NeuroPsychopharmacol. & Biol. Psychiat. 1990, 14 : 879–884. 1. 1. Thirty-two male schizophrenic patients participated in this study. 2. 2. Plasma concentrations of the dopamine metabolite, homovanillic acid (pHVA) were assessed once on neuroleptic medication and twice a week for a maximum of six weeks after its discontinuation. 3. 3. Psychiatric symptomatology was assessed once on neuroleptic medication and once a week for a maximum of six weeks after its discontinuation, using the brief psychiatric rating scale (BPRS). 4. 4. pHVA and total BPRS score increased significantly after discontinuation of neuroleptic as compared to baseline. 5. 5. The magnitude of pHVA and BPRS increments after discontinuation of neuroleptic correlated significantly. 6. 6. Results of this study suggest that worsening of schizophrenic symptoms after discontinuation of neuroleptic treatment is associated with increased pHVA concentrations.

Clonazepam in treatment of bipolar psychotic patients after discontinuation of neuroleptics

Clonazepam in treatment of bipolar psychotic patients after discontinuation of neuroleptics

The effect of neuroleptic discontinuation on psychopathology, involuntary movements, and biochemical measures in patients with persistent tardive dyskinesia

As some of the pharmacological activities of neuroleptic medication may involve pathophysiological mechanisms underlying schizophrenia and tardive dyskinesia (TD), it is useful to study patients undergoing medication discontinuation. In this study, 19 stable, neuroleptic-maintained patients with persistent TD underwent taper and discontinuation of their neuroleptic medication over a 3-week period, and multiple behavioral and biochemical (plasma HVA, MHPG, and prolactin) measures were obtained. The major finding was that early relapsing patients had lower baseline and a significantly greater increase in plasma HVA levels after discontinuation than nonrelapsing patients. In addition, patients exhibiting withdrawal-exacerbated TD had significantly lower plasma MHPG levels than patients not exhibiting this phenomenon. The clinical and pharmacological implications of these findings are discussed.

Clinical predictors of exacerbation during neuroleptic discontinuation

Clinical predictors of exacerbation during neuroleptic discontinuation

Facilitation of neuroleptic-induced perioral movements in rats by hyperglycemia

We have noted the emergence of spontaneous abnormal perioral movements 3-4 days following pinealectomy in drug-naive rats. The severity of these movements peaked at six weeks and then gradually attenuated over the following two months. This suggests that activation of neurochemical compensatory mechanisms may account for the diminution in the severity of perioral movements. Pinealectomy transiently increases plasma MSH levels, and the attenuation of perioral movements may have been associated with normalization of plasma MSH. We hypothesize that hypothalamic dysfunction of MSH-release inhibiting factor (MIF) may result in abnormal MSH levels and contribute to the persistence of tardive dyskinesia (TD) in patients. Since high levels of MSH may be associated with seborrhea, we examined the relation between TD and seborrhea in a schizophrenic patient with mild choreoathetoid movements of the orofacial and upper limb regions. He also had mild seborrheic lesions on the face and scalp. Worsening of TD following neuroleptic discontinuation was associated with marked exacerbation of seborrhea and appearance of extensive scalp dandruff. The simultaneous worsening of TD and seborrhea was reported to have occurred on multiple occasions previously. Neuroleptics increase plasma MSH levels. We propose that the presence of chronic seborrhea in patients receiving long-term neuroleptic treatment may indicate dysfunction of hypothalamic-pituitary regulation of MSH and herald the development of persistent TD.

Ethics of Drug Discontinuation Studies in Schizophrenia-Reply

In Reply.— Chandler suggests that neuroleptic discontinuation studies in patients with schizophrenia are unethical. Though this point of view is understandable, we believe it is not warranted and does not reflect a comprehensive understanding of the relevant issues. The efficacy of neuroleptics in schizophrenia is proved but is limited by several factors, perhaps most significantly by the capacity of neuroleptics to cause tardive dyskinesia. In addition, there is marked variability in the course of illness among schizophrenic patients. 1 This is evident in the maintenance treatment literature, which shows that many patients (approximately 30%) relapse despite receiving neuroleptic medication, while neuroleptics can be withdrawn from other patients for many months and in some cases for years without relapse. 2,3 Standard maintenance medication treatment strategies, though they are indisputably effective in group comparisons, may be quite inefficient in addressing the treatment requirements of the individual patient. This has prompted the targeted

Antipsychotic withdrawal phenomena in the medical-surgical setting

The literature describing nondyskinetic antipsychotic withdrawal symptoms is reviewed. The withdrawal of antipsychotic agents can result in nausea, emesis, anorexia, diarrhea, rhinorrhea, diaphoresis, myalgias, paresthesias, anxiety, agitation, restlessness, and insomnia. Psychotic relapse is often presaged by increased anxiety, agitation, restlessness, and insomnia. However, the temporal relationship of these prodromal symptoms to reduction in the dosage or discontinuation of neuroleptics distinguishes them from the effects of abrupt withdrawal.

Chronic neuroleptics alter the effects of the D1 agonist SK&F 38393 and the D2 agonist LY171555 on oral movements in rats.

Vacuous oral movements (OMs) in rats chronically administered haloperidol (HAL), fluphenazine (FLU), or no drug were studied following injections of one of three doses of either a D1 agonist (SK&F 38393) or a D2 agonist (LY171555). Oral movements were observed via closed-circuit television and simultaneously recorded using a computerized video analysis system which measured the distance between two fluorescent dots painted above and below the rat's mouth. SK&F 38393 induced a dose-dependent increase in tremorous oral movements and repetitive chewing movements in the controls; this effect was more pronounced in rats treated with chronic HAL or FLU, both during chronic neuroleptic treatment and even more so when they were tested after drug withdrawal following 5 or 14 months of chronic neuroleptic administration. Conversely, LY171555 produced an inhibition of oral activity at all dose levels in controls. This inhibition was attenuated during chronic administration of HAL or FLU, but returned to control levels (without any signs of supersensitivity) when the animals were retested shortly after discontinuation of neuroleptics. These results indicate that heightened oral movements in rodents following chronic neuroleptic administration can be more clearly induced by D1 than by D2 receptor activation.

Subtle and underrecognized side effects of neuroleptic treatment in children with Tourette's disorder

A variety of side effects developed in children treated with neuroleptics for Tourette's disorder. Of 208 children, 34 manifested dose-related symptoms of dysphoria, nine experienced a worsening of symptoms of Tourette's disorder that was attributed to akathisia, five became hostile and aggressive, three developed "fog states" that disappeared with discontinuation of neuroleptics or treatment with primidone, and three experienced symptoms of tardive dyskinesia that resolved with time. This data base of neuroleptic-treated children with Tourette's disorder demonstrates a variety of subtle and underrecognized side effects that may not be as readily discernible in children receiving neuroleptics for a primary psychiatric disorder.

Antipsychotic withdrawal symptoms: phenomenology and pathophysiology.

The authors review the literature discribing non-dyskinetic antipsychotic withdrawal phenomena. Withdrawal of these agents can cause nausea, emesis, anorexia, diarrhea, rhinorrhea, diaphoresis, myalgia, paresthesia, anxiety, agitation, restlessness, and insomnia. Psychotic relapse is often presaged by increased anxiety, agitation, restlessness and insomnia, but the temporal relationship of these prodromal symptoms to reduction in the dosage or discontinuation of neuroleptics distinguishes them from the effects of abrupt withdrawal.

On the Early Recognition of Neuroleptic Malignant Syndrome

Neuroleptic Malignant Syndrome, a serious and sometimes fatal complication, has been reported to occur in some patients with the administration of neuroleptic medications. Clinically it is manifested by four groups of symptoms which include muscular hypertonicity, autonomic instability, altered consciousness, and hyperthermia. Laboratory findings such as elevated creatinine phosphokinase and leukocytosis are also seen. While it is true that the incidence of the full blown clinical picture of this syndrome is rare, the authors report that only muscular hypertonicity and autonomic instability have occurred frequently in their setting leading to discontinuation of neuroleptics. Such abortive cases may go undetected. If properly diagnosed, the occurrence of this syndrome is not as rare as the published reports indicate. Second, it is reported that rechallenge with neuroleptics may not induce Neuroleptic Malignant Syndrome again. The authors noted recurrence of fever after rechallenge with a different neuroleptic drug. This article describes the method of early recognition and prevention of morbidity as well as mortality.