Traditional Antipsychotic Drugs Research Articles

Modulation of Gut Microbial Diversity through Non-Pharmaceutical Approaches to Treat Schizophrenia.

Schizophrenia (SCZ) is a psychotic syndrome with well-defined signs and symptoms but indecisive causes and effective treatment. Unknown underpinning reasons and no cure of the disease profoundly elevate the risk of illness. Gut microbial dysbiosis related metabolic dysfunction is providing a new angle to look at the potential causes and treatment options for schizophrenia. Because of the number of side effects, including gut dysbiosis, of traditional antipsychotic drugs, new alternative therapeutic options are under consideration. We propose that non-pharmacotherapy using biotherapeutic products could be a potent treatment to improve cognitive impairment and other symptoms of schizophrenia. Use of live microorganisms (probiotics), fibers (prebiotics), and polyphenols alone or in a mixture can maintain gut microbial diversity and improve the two-way relationship of the gut microbiota and the central nervous system. Fiber and polyphenol induced management of gut microbiota may positively influence the gut–brain axis by increasing the level of brain-derived neurotrophic factors involved in schizophrenia. Furthermore, we endorse the need for comprehensive clinical assessment and follow-up of psychobiotic (pro and prebiotics) treatment in mental illness to estimate the level of target recovery and disability reduction in schizophrenia.

Real-Time Functional Magnetic Resonance Imaging Neurofeedback for the Relief of Distressing Auditory-Verbal Hallucinations: Methodological and Empirical Advances.

Auditory-verbal hallucinations (AVH) are often associated with high levels of distress and disability in individuals with schizophrenia-spectrum disorders. In around 30% of individuals with distressing AVH and diagnosed with schizophrenia, traditional antipsychotic drugs have little or no effect. Thus, it is important to develop mechanistic models of AVH to inform new treatments. Recently a small number of studies have begun to explore the use of real-time functional magnetic resonance imaging neurofeedback (rtfMRI-NF) for the treatment of AVH in individuals with schizophrenia. rtfMRI-NF protocols have been developed to provide feedback about brain activation in real time to enable participants to progressively achieve voluntary control over their brain activity. We offer a conceptual review of the background and general features of neurofeedback procedures before summarizing and evaluating existing mechanistic models of AVH to identify feasible neural targets for the application of rtfMRI-NF as a potential treatment. We consider methodological issues, including the choice of localizers and practicalities in logistics when setting up neurofeedback procedures in a clinical setting. We discuss clinical considerations relating to the use of rtfMRI-NF for AVH in individuals distressed by their experiences and put forward a number of questions and recommendations about best practice. Lastly, we conclude by offering suggestions for new avenues for neurofeedback methodology and mechanistic targets in relation to the research and treatment of AVH.

Clozapine-Induced Perimyocarditis

Atypical antipsychotic drugs are widely used in the treatment of schizophrenia due to their higher efficacy and better side-effect profile compared with traditional antipsychotic drugs. However, serious cardiac toxicity of these drugs can occur, and if not recognized early, can be fatal. In this report, we present a case of acute perimyocarditis following the initiation of Clozapine, a frequently used atypical antipsychotic drug, for the treatment of refractory schizophrenia, which completely resolved after the discontinuation of this drug. Key words: Clozapine, Atypical antipsychotic drug, Perimyocarditis.

Modern approaches to treatment of psychosis in Parkinson's disease

Psychotic disorders in Parkinson's disease (PDPD) are common and significantly influence the quality of life and disability level. The pathogenesis of PDPD is complex and not yet fully understood. Taking into consideration the features of the Parkinson's disease (usually older patients with a risk of cognitive decline), and the pharmacodynamics of the antiparkinsonian and traditional antipsychotic drugs, the management of PDPD is a challenging issue of clinical neurology and psychiatry. In this systematic review, scientific publications for the period 2014-2016 were analyzed within two bibliographic databases: MEDLINE/PubMed and eLIBRARY.RU. Additionally, the guidelines of the International Parkinson and Movement Disorders Society, American Academy of Neurology and European Academy of Neurology were included in the analysis. Clozapine is recommended to use in the treatment of PDPD, quetiapine is possible to use, pimavanserin will probably become a remedy of choice. Nonpharmacological approaches have positive effects on the general condition of the patients with PDPD, however the efficacy of such approaches to treat psychosis is unclear.

Serum Glutathione in Patients with Schizophrenia in Dynamics of Antipsychotic Therapy.

Serum concentrations of oxidized and reduced glutathione were measured in 73 patients with schizophrenia at admission and in dynamics of therapy with traditional and atypical antipsychotic drugs. The level of reduced glutathione in patients with schizophrenia with manifest clinical symptoms was lower than in normal subjects. Atypical neuroleptics produced virtually no effects on the glutathione system, while therapy with typical antipsychotics led to further decrease in the levels of reduced glutathione, thus aggravating the imbalance of metabolic processes typical of schizophrenia.

Glucose-6-phosphate dehydrogenase and catalase activities in erythrocytes of schizophrenic patients under pharmacotherapy with traditional antipsychotics

We studied the activities of glucose-6-phosphate dehydrogenase and catalase in erythrocytes of schizophrenia patients who were under pharmacotherapy with traditional antipsychotic drugs. Prior to therapy, we observed decreased activity of glucose-6-phosphate dehydrogenase and increased activity of catalase in patients compared to the control. After a 6-week therapy with antipsychotics of the first generation, catalase activity became normal, whereas the activity of glucose-6-phosphate dehydrogenase declined further.

Pharmacological treatment of schizophrenia: a critical review of the pharmacology and clinical effects of current and future therapeutic agents

Since the introduction of chlorpromazine and throughout the development of the new-generation antipsychotic drugs (APDs) beginning with clozapine, the D(2) receptor has been the target for the development of APDs. Pharmacologic actions to reduce neurotransmission through the D(2) receptor have been the only proven therapeutic mechanism for psychoses. A number of novel non-D(2) mechanisms of action of APDs have been explored over the past 40 years but none has definitively been proven effective. At the same time, the effectiveness of treatments and range of outcomes for patients are far from satisfactory. The relative success of antipsychotics in treating positive symptoms is limited by the fact that a substantial number of patients are refractory to current medications and by their lack of efficacy for negative and cognitive symptoms, which often determine the level of functional impairment. In addition, while the newer antipsychotics produce fewer motor side effects, safety and tolerability concerns about weight gain and endocrinopathies have emerged. Consequently, there is an urgent need for more effective and better-tolerated antipsychotic agents, and to identify new molecular targets and develop mechanistically novel compounds that can address the various symptom dimensions of schizophrenia. In recent years, a variety of new experimental pharmacological approaches have emerged, including compounds acting on targets other than the dopamine D(2) receptor. However, there is still an ongoing debate as to whether drugs selective for singe molecular targets (that is, 'magic bullets') or drugs selectively non-selective for several molecular targets (that is, 'magic shotguns', 'multifunctional drugs' or 'intramolecular polypharmacy') will lead to more effective new medications for schizophrenia. In this context, current and future drug development strategies can be seen to fall into three categories: (1) refinement of precedented mechanisms of action to provide drugs of comparable or superior efficacy and side-effect profiles to existing APDs; (2) development of novel (and presumably non-D(2)) mechanism APDs; (3) development of compounds to be used as adjuncts to APDs to augment efficacy by targeting specific symptom dimensions of schizophrenia and particularly those not responsive to traditional APD treatment. In addition, efforts are being made to determine if the products of susceptibility genes in schizophrenia, identified by genetic linkage and association studies, may be viable targets for drug development. Finally, a focus on early detection and early intervention aimed at halting or reversing progressive pathophysiological processes in schizophrenia has gained great influence. This has encouraged future drug development and therapeutic strategies that are neuroprotective. This article provides an update and critical review of the pharmacology and clinical profiles of current APDs and drugs acting on novel targets with potential to be therapeutic agents in the future.

Indicators of Conformance With Guidelines of Schizophrenia Treatment in Mental Health Services

The aim of this study was to develop indicators of conformance in clinical practice with guidelines for care in schizophrenia. Recommended guidelines rarely apply to all patients and need to allow for social ability, family context, and phase of the disorder. These indicators were therefore devised for tailoring to patient characteristics and allowing for factors that may justify the lack of adherence to clinical guidelines. A team of senior clinicians and methodologists reviewed three clinical guidelines (from the Schizophrenia Patient Outcomes Research Team, McEvoy and colleagues, and the National Institute for Health and Clinical Excellence) and defined criteria for their operationalization into clinical indicators. For each indicator, the team defined criteria for eligibility (requirements to be met to qualify for evaluation), conformance (criteria to be satisfied to comply with each recommendation), and moderators (factors that could justify the lack of application of a given recommendation). These indicators were tested with a random sample of 807 patients with schizophrenia or schizoaffective disorders in outpatient facilities, long-term residential facilities, and hospital units for acute care in the Piedmont region of Italy. A set of 15 indicators was derived, nine concerning pharmacological treatment and six for general care and psychosocial rehabilitation. Moderators such as patient or family refusal of antipsychotic treatment and the patient's level of disability helped to justify a considerable proportion of nonconformant care. The indicators developed are a simple and useful tool to monitor the conformance of care with recommended practices and to identify areas needing improvement.

Indicators of Conformance With Guidelines of Schizophrenia Treatment in Mental Health Services

Indicators of Conformance With Guidelines of Schizophrenia Treatment in Mental Health Services

Commentary on strategies for switching antipsychotics

Both the new generation of antipsychotics and the more traditional antipsychotic drugs produce an important and meaningful improvement in patients with schizophrenia, but most patients are neither cured nor free of symptoms. As a consequence, it is common to switch from one drug to another in the hope of obtaining a better response. All antipsychotic drugs produce some side effects, so switching can also be a tolerance issue. There are reports in the literature on the tactics of switching: abrupt discontinuation, cross tapering, starting a patient on a new drug while continuing with the old drug until the new drug has reached a steady state, or some variation on these tactics. In this issue, Ganguli et al. have carried out a randomized switching study, the data from which indicates the tactics that might be optimal. We put this paper into context, provide a critique and describe indications for switching.

A Case of Metoclopramide-induced Oculogyric Crisis in a 16-year-old Girl with Cystic Fibrosis

Oculogyric crisis is a neurologic reaction characterized by bilateral dystonic elevation of visual gaze as well as hyperextension of the neck. This reaction is most commonly explained as an adverse effect of numerous medications, such as dopamine receptor blocking agents or neuroleptic medications and traditional antipsychotic or antiemetic drugs, such as prochlorperazine or metoclopramide. A case of oculogyric crisis induced by metoclopramide is described in this paper.

Effectiveness and Safety of Risperidone for Children and Adolescents with Chronic Tic or Tourette Disorders in Korea

The aim of this 6-week, open-label design study was to determine the short-term effectiveness and safety of risperidone as an alternative for traditional antipsychotic drugs in the treatment of chronic tic disorder or Tourette's Disorder in young children and adolescents. The subjects were 15 young children and adolescents (the ratio of male:female subjects was 13:2 and their mean age was 10 +/- 2.4 years). Seven subjects were diagnosed with Tourette's Disorder and 8 subjects with chronic tic disorder, and all subjects were administered risperidone without hospitalization. Of the 15 subjects, 1 subject had a comorbid disorder (obsessive compulsive disorder), but no subject had a previous history of psychiatric hospitalization. Ten of the 15 subjects were administered risperidone for the first time, and 5 of the 15 subjects had been previously treated with traditional drugs (haloperidol or pimozide). Clinical responses were measured at baseline and after 1, 3, and 6 weeks of drug treatment by using the Korean version of the Yale Global Tic Severity Scale and the Global Assessment of Functioning Scale. Side effects were carefully monitored using adverse event evaluation charts. The mean dosage of risperidone was 0.53 +/- 0.13 mg on the 1st week, 0.90 +/- 0.28 mg on the 3rd week, and 1.23 +/- 0.37 mg on the 6th week. Comparison between periods according to the Korean version of the Yale Global Tic Severity Scale showed significant differences (t = 4.920; df = 14; p < 0.01) during the 1st- to 3rd-week period. After 6 weeks of administration, the tic severity scale showed a 36% reduction in the overall tic symptom scores and 13 of the 15 subjects showed significant improvement, 1 subject showed no difference in symptoms, and, for 1 subject, the symptoms worsened. Also, the mean Global Assessment of Functioning Scale score was 66.8 +/- 10.8 at baseline and improved to a mean of 73.1 +/- 10.1 after 6 weeks of treatment. Regarding side effects, only 1 case reported sedation, but drug administration was continued because the degree was mild. The results of this study show that, risperidone, a potent combined serotonin (5-HT2) and dopamine (D2) receptor antagonist, is both effective and safe for the treatment for Tourette's Disorder and chronic tic disorder in children and adolescents.

Antidepressants and antipsychotics

Although there is still debate over the biochemical basis of depression, most drugs that are effective in this disorder potentiate the actions of noradrenaline or serotonin (5-HT). The main mechanisms of this action are prevention of reuptake and inhibition of metabolism. However, the delay in obtaining relief from symptoms suggests that biochemical effects downstream from this acute action are responsible for the beneficial effects. Mood stabilizers, which are used to treat manic depression, include lithium salts and the anticonvulsant carbamazepine. Most traditional antipsychotic drugs are antagonists at D2 receptors and cause extrapyramidal side-effects as a consequence. Atypical drugs, which have fewer extrapyramidal effects, appear to cause additional blockade of 5-HT 2 receptors.

Effect of haloperidol and risperidone on amyloid precursor protein levels in vivo

The neurotoxic β-amyloid peptide of Alzheimer’s disease is formed from the amyloid precursor protein (APP), which is a member of an evolutionarily highly conserved gene family with significant functional importance. Because behavioral and psychiatric symptoms treated with antipsychotics may influence the course of the disease, we have investigated traditional and atypical antipsychotic drugs, administered through the intraperitoneal route, for their effects on rat cortical APP. Western-immunoblotting was utilized for semi-quantitative evaluation of APP levels. Treatment with haloperidol resulted in an acute elevation of cortical APP both in therapeutic and toxic doses, however, it had no significant chronic impact on APP. Atypical antipsychotic risperidone did not change cortical APP concentration. These results indicate that both haloperidol and risperidone are considered to be relatively safe with respect to APP metabolism. Possible mechanisms, including involvement of calcium and APP itself as a receptor, are discussed.

Traditional and new antipsychotic drugs differentially alter neurotransmission markers in basal ganglia‐thalamocortical neural pathways

The effects of three chronically administered antipsychotic drugs on selected neurochemical markers of dopaminergic and GABAergic transmission were compared within the cerebral regions making up the basal ganglia-thalamocortical parallel processing neuronal pathways. All three drugs reduce psychosis in humans, whereas only haloperidol, but not olanzapine or sertindole, induce purposeless oral chewing movements (CMs) in rats or cause high rates of parkinsonism or tardive dyskinesia in humans. Male Sprague Dawley rats were treated with haloperidol, sertindole, or olanzapine delivered in drinking water for 6 months at doses which produce drug plasma levels in rat in the human therapeutic range. Results show the expected dopamine D2 receptor upregulation in striatum predominantly with haloperidol, although mild D2 upregulation was apparent in striatum after olanzapine. GAD67 mRNA was increased in striatum and decreased in globus pallidus by haloperidol and sertindole, but not by olanzapine. In the substantia nigra pars reticulata (SNR), both olanzapine and sertindole failed to induce GABAA receptor upregulation or D1 receptor downregulation, but haloperidol did both, confirming a previous report. In thalamus, all three drugs increased GAD expression in the reticular nucleus, whereas only haloperidol decreased GABAA binding in the mediodorsal nucleus, actions consistent with a reduction in nigrothalamic, GABA-mediated neural transmission. These results are consistent with the idea that the two new antipsychotics tested have mild and regionally restricted actions within the basal ganglia nuclei and a common action on increasing GAD expression in the reticular nucleus of the thalamus (RtN). Haloperidol, in contrast, has a broad and potent action in basal ganglia, causing changes in SNR and in the mediodorsal nucleus, while also altering GAD mRNA in RtN, potentially reflective of its dyskinetic and antipsychotic actions. Synapse 39:152–160, 2001. © 2001 Wiley-Liss, Inc.

Treatment mechanisms: traditional and new antipsychotic drugs

The first generation of antipsychotic drugs was discovered in the 1960s and 1970s, These agents were effective in treating psychosis, but were accompanied by significant side effects, including severe parkinsonism and akathisia. Second-generation antipsychotics were introduced in the 1990s, These drugs have at least equal efficacy to their predecessors, but far fewer side effects. Some data suggest a broader efficacy profile. Clozapine remains the only superior antipsychotic in terms of the magnitude of psychotic symptom reduction. Clinical and animal studies are consistent in suggesting that the antipsychotic component of antidopaminergic treatments is initiated by dopamine receptor blockade in the striatum and that the signal is transmitted to the neocortex through the established basal ganglia-thalamo-cortical neuronal circuits. Other neurotransmitter actions (eg, antiserotonergic) can be exerted locally, in the neocortex. Defining tissue targets of drug action may suggest additional strategies for developing new antipsychotic drugs.

Sertindole is associated with a low level of extrapyramidal symptoms in schizophrenic patients: Results of a phase III trial

OBJECT: The objective of this double-blind, multicentre study was to evaluate four doses of sertindole and haloperidol 10 mg. METHOD: The 617 schizophrenic patients were randomized to receive sertindole 8, 16, 20 or 24 mg/day or haloperidol 10 mg/day. Patients were assessed for extrapyramidal symptoms (EPS) using the Simpson-Angus Scale (SAS) and Barnes Akathisia Scale (BAS), and for movement disorders using the Abnormal Involuntary Movement Scale (AIMS). RESULTS: Patients receiving haloperidol experienced significantly more EPS than patients receiving sertindole, supporting observations made in previous studies. The incidence of adverse events was similar for all doses of sertindole. SAS and BAS scores were significantly worse in the haloperidol group than in the sertindole groups. There were significantly greater increases in mean QT c interval in the sertindole groups than in the haloperidol group. Sertindole did not cause sedation. CONCLUSIONS: Sertindole is well tolerated and does not cause the debilitating EPS associated with traditional antipsychotic drugs. (Int J Psych Clin Pract 2000; 4:47-54)

Atypical antipsychotics in persons with developmental disabilities

The introduction of clozapine spawned the development of several novel antipsychotic agents during the last decade. Compared to traditional agents, these “atypical antipsychotics” demonstrate more favorable characteristics in terms of efficacy and medication-associated abnormal involuntary movements. Several underlying neurochemical mechanisms have been posited for the differences noted between traditional and atypical antipsychotic drugs. Most theories have been based on the observation that atypical agents have higher affinities and greater selectivity for different dopamine receptor subtypes and for serotonin receptors. In addition, there is speculation about the involvement of other types of neurotransmitters (e.g., γ-aminobutyric acid, N-methyl-d-aspartate) in the actions of these drugs. A review of the current literature on the developmental disabilities indicated that the study populations can be divided into three general categories: (a) individuals with mental retardation and a psychiatric syndrome; (b) individuals with mental retardation and behavioral problems; and (c) individuals with autism and other pervasive developmental disorders. The atypical antipsychotics most consistently appeared to reduce symptoms of self-injury, aggression, agitation, and repetitive behaviors. It is not yet clear whether they enhance prosocial behavior, although findings of some reports suggested this. A clear limitation of the available evidence is that few studies are methodologically sound. Suggestions for further research are offered. MRDD Research Reviews 1999;5:253–263. © 1999 Wiley-Liss, Inc.

Auditory hallucinations: a review of psychological treatments

Auditory hallucinations (AH) occur frequently amongst psychiatric patients, being most common in schizophrenia. In 25–30% of cases they are refractory to traditional antipsychotic drugs. A variety of psychosocial treatments have been used, but their efficacy remains unclear. This review aims to bring together the more recent studies of psychological treatments and discuss them in the context of recent cognitive models of hallucinations and functional imaging studies. The search strategy included the following sources: MEDLINE, Embase and Psychlit. Strategies reported by patients can be categorised as: (1) distracting activities, such as listening to music; (2) behavioural tasks, such as taking exercise; (3) cognitive tasks, such as ignoring AH. Almost all the strategies produced some benefit in some patients; treatment often improved AH-associated distress, rather than frequency of AH. There are many difficulties in conducting research on AH. Treatment should be individually tailored and used as an adjunct to pharmacotherapy. Future theory-driven studies need to be based on complex aetiological models and incorporate functional imaging to elucidate the physiological changes induced by therapeutic interventions.

Clozapine treatment in Australia: a review of haematological monitoring.

Clozapine is an atypical antipsychotic drug indicated for patients with schizophrenia in whom traditional antipsychotic drugs (such as haloperidol or the phenothiazines) are ineffective, or in those who experience intolerable adverse effects. Clozapine treatment may be complicated by the development of life-threatening agranulocytosis, so regular haematological monitoring is required. To determine the incidence of clozapine-induced agranulocytosis in Australia and the importance of monitoring white blood cell counts in patients treated with clozapine. Review of haematological monitoring for the first three years (June 1993-July 1996) of operation of the Australian Clozaril (clozapine; Novartis Australia) Patient Monitoring System (CPMS) central database. In the 4061 patients prospectively monitored by the CPMS, the incidence of agranulocytosis, neutropenia and leukopenia combined was 2.6% (n = 104); the incidence of agranulocytosis was 0.9% (n = 37). So far there have been no deaths in Australia from the complications of clozapine-induced agranulocytosis. The incidence of agranulocytosis and neutropenia associated with clozapine use in Australia is similar to that in the rest of the world. Monitoring the white blood cell counts of patients being treated with clozapine ensures minimal risk to patients who develop agranulocytosis.