clozapine and Psychomotor-Agitation

Akathisa is one of the most common and distressing neuroleptic-induced extrapyramidal side effects. Although it is well recognized in the context of conventional antipsychotic medications, there have been recent concerns raised by clinicians and researchers that this syndrome is overlooked in relation to second-generation or atypical antipsychotics. This review examines the recent literature relevant to second-generation antipsychotic (SGA)-induced akathisia.. Recent studies using large databases clearly indicate that extrapyramidal side effects, in particular akathisia, do occur with the SGAs, although the frequency is not as high as with the conventional antipsychotics. Risk factors include use of high doses, high potency SGAs, or combinations of SGAs with other psychotropic drugs, bipolar depression, palliative care settings, and comorbid substance abuse in psychosis. The dopamine hypothesis remains plausible for understanding the pathophysiology of akathisia. There is emerging evidence that mirtazapine may be useful in the treatment of acute akathisia.. Even though akathisia is less prevalent with SGAs than with the first-generation drugs, it remains clinically important and all clinicians should be conversant with its recognition and management.

Topics: Amisulpride; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Clozapine; Dibenzothiazepines; Humans; Isoxazoles; Olanzapine; Piperazines; Piperidines; Prevalence; Psychomotor Agitation; Psychotic Disorders; Quetiapine Fumarate; Quinolones; Risk Factors; Risperidone; Sulpiride; Thiazoles

Akathisia (restlessness and characteristic movements of the legs) is one of the most disagreeable extrapyramidal side effects and often causes non-compliance. Dopamine blocking agents such as antipsychotics and antiemetics, may induce akathisia. Particular care must be taken to distinguish akathisia from psychotic agitation and restless legs. The prevalence of akathisia in patients using classical antipsychotics is 20-30% and for users of clozapine, olanzapine and quetiapine (atypical antipsychotics) it is lower. Risk factors are a high dosage of antipsychotics, akathisia in a previous treatment, and diabetes mellitus. The treatment of akathisia starts, if possible, with the antipsychotic being withdrawn or the dose administered being lowered. Another treatment possibility is switching to clozapine, olanzapine or quetiapine, or adding a beta-blocking agent, an anticholinergic or mianserin.

Topics: Akathisia, Drug-Induced; Antipsychotic Agents; Benzodiazepines; Clozapine; Diabetes Complications; Diagnosis, Differential; Dibenzothiazepines; Dose-Response Relationship, Drug; Humans; Olanzapine; Pirenzepine; Prevalence; Psychomotor Agitation; Quetiapine Fumarate; Recurrence; Restless Legs Syndrome; Risk Factors

For patients hospitalized with acute episodes of psychosis, rapid stabilization of intense positive symptoms, hostility, and agitation is typically a preeminent therapeutic goal. These goals often differ from those of the nonhospitalized patient with psychosis for whom long-term treatment goals such as improvement of negative symptoms, cognitive function, compliance, and reduction in side effect burden may be paramount. Therefore, when selecting an antipsychotic treatment for hospitalized patients, efficacy against positive symptoms and hostility as well as speed of therapeutic onset should strongly be considered. At the same time, selection of antipsychotic treatment in the inpatient setting should establish a definitive treatment that will address long-term goals effectively after discharge. This article presents the rationale and practical guidelines for selection of treatment regimens for patients hospitalized due to acute psychosis.

Topics: Acute Disease; Antipsychotic Agents; Benzodiazepines; Clozapine; Drug Administration Schedule; Drug Therapy, Combination; Haloperidol; Hospitalization; Hostility; Humans; Olanzapine; Pirenzepine; Practice Guidelines as Topic; Psychomotor Agitation; Psychotic Disorders; Risperidone; Treatment Outcome

The management of agitation and aggression in psychiatric inpatients is a significant clinical dilemma. Establishing a clear diagnosis and distinguishing whether aggression is an acute manifestation or a long-standing or repetitive problem are fundamental antecedents of medication treatment. For acute aggression, either benzodiazepines or antipsychotic medications (typical and atypical) are recommended choices. Currently, on the basis of efficacy, ease of use, and availability in multiple (tablet, liquid, intramuscular) preparations, typical antipsychotics such as loxapine should be considered as first choice for acute aggression (in psychosis). On the other hand, atypical antipsychotics, particularly clozapine, should be considered when aggression in psychosis persists and/or is repetitive. Typical antipsychotics are indicated for persistent aggression in psychosis when medication noncompliance is the obstacle to effective treatment.

Topics: Aggression; Antipsychotic Agents; Benzodiazepines; Clozapine; Humans; Loxapine; Mental Disorders; Olanzapine; Pirenzepine; Psychomotor Agitation; Psychotic Disorders; Risperidone; Schizophrenia; Schizophrenic Psychology

Sundowning refers to episodes of agitated behaviour that are more frequent or are more severe at night. Although the effects of different psychoactive medications on agitated behaviour in dementia patients have been documented in hundreds of reports over the last 30 years, less than 20 studies make explicit reference to time of day for which outcome measures were derived, and even fewer have also examined sleep as an outcome. Thus, despite varying claims of efficacy and effectiveness for various medications, there are few data to support informed management of disruptive nocturnal behaviour in these patients. In this brief article, we selectively review those few studies explicitly mentioning temporal dimensions of behavioural outcome, including some newer studies of unconventional types of treatment that may be useful for the treatment of sundowning. We conclude that future pharmacological studies should systematically assess behaviour throughout the 24-hour day to provide outcome data relevant to this phenomenon.

Topics: Antipsychotic Agents; Chlormethiazole; Clozapine; Dementia; Humans; Melatonin; Phototherapy; Psychomotor Agitation

Symptoms of generalized anxiety disorder are commonly observed in elderly persons and especially in those suffering from dementia. In the demented elderly, these symptoms are often defined as agitation. Approximately 60% of demented persons will present with symptoms of agitation at some point during the course of their illness. The presence of agitation has devastating consequences for the patient and the caregiver. This paper reviews some of the existing literature with regard to the etiology and treatment of agitation in the demented elderly. Agitated behaviors are generally divided in three categories (verbal agitation physically nonaggressive agitation, and aggressive agitation). It is suggested that each category may have a different etiology and treatment; verbal agitation is often related to underlying medical conditions, physically nonaggressive behavior responds to behavioral treatment, and aggressive agitation is more likely to respond to a combination of behavioral and pharmacologic treatment.

Topics: Aged; Aggression; Antipsychotic Agents; Anxiety Disorders; Behavior Therapy; Buspirone; Carbamazepine; Clozapine; Combined Modality Therapy; Decision Trees; Dementia; Humans; Ondansetron; Psychomotor Agitation; Serotonin; Trazodone

Agitation or psychosis or both occur in half or more of patients with dementia at some point during the course of illness. The treatment of these signs and symptoms ideally entails identification and alteration of physical, environmental, social, and psychiatric factors. Environmental modification, education of caregivers, and therapeutic activity programs are nonpharmacologic approaches that can effectively reduce some signs and symptoms of this nature. For those that remain, empirical administration of pharmacologic agents may be appropriate. One approach is to inventory the specific behaviors and develop a "therapeutic metaphor," i.e., subtype the agitated behaviors according to the presence of target symptoms likely to respond to specific classes of medication. Available evidence is reviewed regarding the efficacy and safety of somatic therapies for agitation, including antipsychotics, antidepressants, anticonvulsants, benzodiazepines, and cholinesterase inhibitors.

Topics: Aged; Anti-Anxiety Agents; Anticonvulsants; Antidepressive Agents; Antipsychotic Agents; Clozapine; Dementia; Humans; Psychomotor Agitation; Psychotic Disorders; Risperidone; Selective Serotonin Reuptake Inhibitors; Trazodone

Topics: Adult; Aggression; Clozapine; Fatal Outcome; Female; Heart Failure; Humans; Psychiatric Department, Hospital; Psychomotor Agitation; Psychotic Disorders; Restraint, Physical

Serotonin 5-HT. Locomotor activity was tested in mGlu2-KO mice and control littermates injected (i.p.) with clozapine (1.5 mg/kg) or vehicle followed by MK801 (0.5 mg/kg), PCP (7.5 mg/kg), amphetamine (6 mg/kg), scopolamine (2 mg/kg), or vehicle. Using a virally (HSV) mediated transgene expression approach, the role of frontal cortex mGlu2 in the modulation of MK801-induced locomotor activity by clozapine treatment was also evaluated.. The effect of clozapine on hyperlocomotor activity induced by the dissociative drugs MK801 and phencyclidine (PCP) was decreased in mGlu2-KO mice as compared to controls. Clozapine treatment, however, reduced hyperlocomotor activity induced by the stimulant drug amphetamine and the deliriant drug scopolamine in both wild-type and mGlu2-KO mice. Virally mediated over-expression of mGlu2 in the frontal cortex of mGlu2-KO mice rescued the ability of clozapine to reduce MK801-induced hyperlocomotion.. These findings further support the existence of a functionally relevant crosstalk between 5-HT

Topics: Animals; Antipsychotic Agents; Clozapine; Frontal Lobe; Male; Mice; Mice, Knockout; Phencyclidine; Psychomotor Agitation; Psychotic Disorders; Receptor, Serotonin, 5-HT2A; Receptors, Metabotropic Glutamate; Schizophrenia

Topics: Adult; Antipsychotic Agents; Clozapine; Female; Humans; Psychomotor Agitation; Psychotic Disorders; Time Factors

Dopaminergic systems have been known to be involved in the regulation of locomotor activity and development of psychosis. However, the observations that some Parkinson's disease patients can move effectively under appropriate conditions despite low dopamine levels (eg, kinesia paradoxia) and that several psychotic symptoms are typical antipsychotic resistant and atypical antipsychotic sensitive indicate that other systems beyond the dopaminergic system may also affect locomotor activity and psychosis. The present study showed that dopamine-deficient (DD) mice, which had received daily L-DOPA injections, could move effectively and even be hyperactive 72 h after the last L-DOPA injection when dopamine was almost completely depleted. Such hyperactivity was ameliorated by clozapine but not haloperidol or ziprasidone. Among multiple actions of clozapine, muscarinic acetylcholine (ACh) activation markedly reduced locomotor activity in DD mice. Furthermore, the expression of choline acetyltransferase, an ACh synthase, was reduced and extracellular ACh levels were significantly reduced in DD mice. These results suggest that the cholinergic system, in addition to the dopaminergic system, may be involved in motor control, including hyperactivity and psychosis. The present findings provide additional evidence that the cholinergic system may be targeted for the treatment of Parkinson's disease and psychosis.

Topics: Acetylcholine; Akathisia, Drug-Induced; Animals; Anti-Dyskinesia Agents; Antipsychotic Agents; Central Nervous System Stimulants; Choline O-Acetyltransferase; Clozapine; Corpus Striatum; Disease Models, Animal; Dopamine; Dopamine Agents; Extracellular Space; Haloperidol; Levodopa; Locomotion; Mice, Inbred C57BL; Piperazines; Psychomotor Agitation; Thiazoles

Recently, a novel paradigm has been designed to assess social investigative behaviour in pairs of Sprague-Dawley rats, which involves physical separation whilst ensuring they are able to maintain contact through other social cues. We have modified this set-up in order to assess not just social behaviour but also locomotor activity of the rats. Results showed that the MK-801- (0.3 mg/kg) treated rats displayed reduced social investigative behaviour, hyperactivity as well as reduced attention span. Pretreatment with the phytocannabinoid cannabidiol (3 mg/kg) not only normalised social investigative behaviour but increased it beyond control levels. Pretreatment with clozapine (1, 3 mg/kg) also normalised social investigative behaviour. Both cannabidiol and clozapine inhibited MK-801-induced hyperactivity. However, there were no effects of pretreatment on impairments to attention span. Our findings reinforce several aspects of the validity of the MK-801-induced model of social withdrawal and hyperactivity and also support the use of this novel set-up for further investigations to assess the antipsychotic potential of novel compounds.

Topics: Animals; Antipsychotic Agents; Attention; Attention Deficit Disorder with Hyperactivity; Behavior, Animal; Cannabidiol; Clozapine; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Male; Motor Activity; Psychomotor Agitation; Psychotropic Drugs; Rats; Rats, Sprague-Dawley; Schizophrenia; Social Behavior; Social Behavior Disorders

Topics: Antipsychotic Agents; Benzodiazepines; Chronic Disease; Clozapine; Cognition Disorders; Dementia; Drug Resistance; Humans; Korsakoff Syndrome; Male; Middle Aged; Neuropsychological Tests; Psychomotor Agitation; Schizophrenia

Few studies have examined the potential role of clozapine in treatment of agitation in dementia patients who have previously failed to respond to standard pharmacotherapy. We conducted a systematic chart review of all elderly patients admitted to our inpatient unit between 2001 and 2004. Of them, 16 dementia patients were treated with clozapine for treatment-resistant agitation, and their charts were blindly rated by 3 clinicians on the Clinical Global Impression (CGI) Scale, Brief Agitation Rating Scale (BARS), and the Cohen-Mansfield Agitation Inventory-Short Form (CMAI-SF). Overall, clozapine therapy seemed beneficial in treatment-resistant agitation in dementia patients.

Topics: Aged; Antipsychotic Agents; Clozapine; Dementia; Drug Resistance; Female; Geriatric Assessment; Humans; Male; Observer Variation; Psychiatric Status Rating Scales; Psychomotor Agitation; Severity of Illness Index; Treatment Outcome

The authors report a case of a patient, who in a few days after an abrupt discontinuation of clozapine and haloperidol developed agitated and confused state resembling neuroleptic malignant syndrome (NMS) and clozapine withdrawal symptoms at the same time. Data obtained from family members led to gradual reintroduction of clozapine and to subsequent recovery. The case illustrates the importance for clinicians to be familiar with the variety of discontinuation symptoms, so they can recognize them and offer effective treatment.

Topics: Adult; Antipsychotic Agents; Clozapine; Haloperidol; Humans; Male; Neuroleptic Malignant Syndrome; Psychomotor Agitation; Substance Withdrawal Syndrome; Treatment Refusal

We report the case of a patient with schizophrenia, who experienced agranulocytosis during clozapine treatment, followed by bronchopulmonal infection and Guillain-Barré syndrome. The case was recorded within the German surveillance project "drug safety in psychiatry" (AMSP).

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Female; Guillain-Barre Syndrome; Humans; Middle Aged; Psychomotor Agitation; Respiratory Tract Infections; Schizophrenia; Sepsis

A new diaryl-methylene piperidine derivative, 2, displayed an atypical antipsychotic profile both in vitro and in vivo. The main pharmacological characteristics of this compound appears to reside in a more potent antagonism of the 5-HT2 serotonergic receptor than of the D2 dopaminergic receptor. This confirms that molecules displaying a D2/5-HT2 binding ratio < 1 possess clozapine-like antipsychotic activity.

Topics: Animals; Antipsychotic Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Mice; Piperidines; Protein Binding; Psychomotor Agitation; Psychotic Disorders; Receptors, Dopamine D2; Receptors, Serotonin; Serotonin Antagonists

Akathisia is one of the most distressing side effects of neuroleptic treatment. It is usually managed by manipulating the neuroleptic dose and administering anti-akathisic compounds (beta-blockers, anticholinergics, serotonin antagonists). However, the pathophysiological background of withdrawal akathisia which follows the discontinuation of neuroleptic treatment remains unclear, and there is as yet no adequate treatment. We report a case of severe withdrawal akathisia associated with suicidal and autoaggressive behaviour during a gradual transition from perphenazine/trihexyphenidyl to clozapine. The akathisia was effectively managed by titration of clozapine (maximum dose 200 mg/day) Thereafter, reduction of the clozapine dose resulted in a recurrence of the akathisia, and the resumption of clozapine dose was accompanied by full amelioration of symptoms. We suggest that the antiserotonergic properties of clozapine were responsible for its anti-akathisic effect. Differences in the treatment of acute and withdrawal types of akathisia are emphasized.

Topics: Adult; Antipsychotic Agents; Clozapine; Humans; Male; Psychomotor Agitation; Schizophrenia; Substance Withdrawal Syndrome

We present the results obtained using low doses of clozapine (mean dose 26.4 mg at bedtime) in the treatment of nocturnal akathisia in nine patients with Parkinson's disease for a mean period of 12.5 months. The results were excellent in all the patients. Furthermore, three patients experienced a remarkable improvement in rest tremor and in five patients the confusional state that accompanied the akathisia also disappeared. No serious side-effects were observed. We believe that clozapine is a very useful drug for the relief of nocturnal akathisia in parkinsonian subjects.

Topics: Adult; Aged; Aged, 80 and over; Benserazide; Carbidopa; Circadian Rhythm; Clozapine; Confusion; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Neurologic Examination; Parkinson Disease; Psychomotor Agitation; Sleep Wake Disorders

Clozapine, an atypical neuroleptic, is an effective medication in a subgroup of schizophrenic patients who have either failed to respond to the typical neuroleptics or experienced intolerable side effects such as neuroleptic malignant syndrome and disabling tardive dyskinesia. Its efficacy for persistent and disabling akathisia is less clear. Akathisia, especially the chronic and disabling form, can be a treatment dilemma for the clinician and the patient.. We describe three representative case illustrations of schizophrenic patients who had severe, persistent treatment-resistant akathisia. Two of them had refractory psychoses and the third had multiple disabling side effects during treatment with typical neuroleptics. Two had tardive dyskinesia. These patients were treated with clozapine while other neuroleptics were discontinued.. During a 2-year follow-up, these patients made impressive social and vocational strides coinciding with a fairly rapid remission of akathisia (under 3 months) and a lesser though notable improvement in the psychoses. Tardive dyskinesia also remitted, though over a period of 6 to 12 months.. Our experience leads us to suggest a trial of clozapine in a subgroup of schizophrenic patients, who in addition to refractory psychoses have persistent disabling akathisia. However, given the risk of agranulocytosis with clozapine, we suggest that the usual treatment strategies for akathisia be tried before clozapine is initiated in the approved manner. Future controlled trials of clozapine that specifically investigate persistent akathisia may answer this question more conclusively.

Topics: Adult; Agranulocytosis; Akathisia, Drug-Induced; Antipsychotic Agents; Chronic Disease; Clozapine; Dyskinesia, Drug-Induced; Female; Follow-Up Studies; Humans; Male; Middle Aged; Psychomotor Agitation; Schizophrenia; Schizophrenic Psychology; Social Adjustment

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.

Topics: Adult; Akathisia, Drug-Induced; Clozapine; Female; Humans; Male; Prevalence; Prognosis; Psychomotor Agitation

Topics: Adult; Akathisia, Drug-Induced; Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Humans; Male; Motor Activity; Neurologic Examination; Psychomotor Agitation; Schizophrenia, Paranoid