clozapine and Parkinsonian-Disorders

Despite treatment advances over the past decades, schizophrenia remains one of the most severe psychiatric disorders that is associated with a chronic relapsing course and marked functional impairment in a substantial proportion of patients. In this article, a historical overview of the pharmacologic advances in the treatment of schizophrenia over the past 50 years is presented. This is followed by a review of the current developments in optimizing the treatment and outcomes in patients with schizophrenia. Methodological challenges, potential solutions, and areas of particular need for further research are highlighted. Although treatment goals of response, remission, and recovery have been defined more uniformly, a good "effectiveness" measure mapping onto functional outcomes is still lacking. Moreover, the field must advance in transferring measurement-based approaches from research to clinical practice. There is an ongoing debate regarding whether and which first- or second-generation antipsychotics should be used. However, especially when considering individual adverse effect profiles, the differentiation into first- and second-generation antipsychotics as unified classes cannot be upheld, and a more differentiated view and treatment selection are required. The desired, individualized treatment approach needs to consider current symptoms, comorbid conditions, past therapeutic response, and adverse effects, as well as patient choice and expectations. Acute and long-term goals and effects of medication treatment should be balanced. To date, clozapine is the only evidence-based treatment for refractory patients, and the role of antipsychotic polypharmacy and other augmentation strategies remains unclear, at best. To discover novel treatments with enhanced/broader efficacy and improved tolerability, and to enable personalized treatment, the mechanisms underlying illness development and progression, symptomatic improvement, and side effect development need to be elucidated.

Topics: Antipsychotic Agents; Chlorpromazine; Clozapine; Controlled Clinical Trials as Topic; Diabetes Mellitus, Type 2; Drug Monitoring; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Evidence-Based Medicine; Humans; Long-Term Care; Metabolic Clearance Rate; Parkinsonian Disorders; Precision Medicine; Psychiatric Status Rating Scales; Research; Schizophrenia; Schizophrenic Psychology; Secondary Prevention; Treatment Outcome

Lewy body dementia and Parkinson disease dementia are frequent causes of degenerative dementia: 20% of the dementias in patients older than 65 years are caused by the former and nearly 80% of patients with advanced Parkinson disease develop the latter. Symptoms of Lewy body dementia include fluctuations of cognitive performance, frontal and visuospatial impairment, visual hallucinations, and parkinsonism. Parkinson disease dementia could be differentiated in two subtypes: a "subcortical" subtype, characterized by frontal impairment with apathy and dullness and a "cortical" subtype with symptoms similar to those of Lewy body dementia. Mastery of potential iatrogenic factors is important: psychotropic drugs must be prescribed at the strict minimum, and L-dopa monotherapy at the minimal dose acceptable for correcting Parkinsonian motor symptoms should be the rule. Acetylcholinesterase inhibitors may be useful in both these types of dementia: rivastigmine is approved for treating Parkinson disease dementia and clozapine for reducing hallucinations.

Topics: Aged; Antiparkinson Agents; Antipsychotic Agents; Cholinesterase Inhibitors; Clozapine; Dementia; Diagnosis, Differential; Disease Progression; Dopamine Agents; Humans; Iatrogenic Disease; Levodopa; Lewy Body Disease; Neuroprotective Agents; Nootropic Agents; Parkinson Disease; Parkinsonian Disorders; Phenylcarbamates; Psychotropic Drugs; Rivastigmine; Serotonin Antagonists

With dopaminergic systems, non dopaminergic neurotransmission probably plays a major role in parkinsonian syndromes (Multiple System Atrophy, Progressive Supranuclear Palsy, Pure Autonomic Failure, Cortical basal degeneration, Lewy Body Disease). A better understanding of the pathophysiology of these syndromes led to the development of molecules that interact with non dopaminergic systems. Thus, freezing, gait and balance disorders, dysautonomia and neuropsychiatric disorders are likely to benefit from specific treatments. However, due to methodological difficulties related to the evaluation of such molecules, controlled trials are rather rare and the results are often partial and sometimes unclear.

Topics: Anti-Dyskinesia Agents; Botulinum Toxins; Cholinesterase Inhibitors; Clozapine; Dementia; Depressive Disorder; Dopamine; Glutamic Acid; Humans; Movement Disorders; Parkinsonian Disorders; Selective Serotonin Reuptake Inhibitors; Serotonin; Synaptic Transmission; Treatment Outcome

Older persons and, more severely, persons with Parkinson's disease (PD) exhibit gait dysfunction, postural instability and a propensity for falls. These dopamine (DA) replacement-resistant symptoms are associated with losses of basal forebrain and striatal cholinergic neurons, suggesting that falls reflect disruption of the corticostriatal transfer of movement-related cues and their striatal integration with movement sequencing. To advance a rodent model of the complex movement deficits of Parkinsonian fallers, here we first demonstrated that male and female rats with dual cortical cholinergic and striatal DA losses (DL rats) exhibit cued turning deficits, modeling the turning deficits seen in these patients. As striatal cholinergic interneurons (ChIs) are positioned to integrate movement cues with gait, and as ChI loss has been associated with falls in PD, we next used this task, as well as a previously established task used to reveal heightened fall rates in DL rats, to broadly test the role of ChIs. Chemogenetic inhibition of ChIs in otherwise intact male and female rats caused cued turning deficits and elevated fall rates. Spontaneous turning was unaffected. Furthermore, chemogenetic stimulation of ChIs in DL rats reduced fall rates and restored cued turning performance. Stimulation of ChIs was relatively more effective in rats with viral transfection spaces situated lateral to the DA depletion areas in the dorsomedial striatum. These results indicate that striatal ChIs are essential for the control of complex movements, and they suggest a therapeutic potential of stimulation of ChIs to restore gait and balance, and to prevent falls in PD.

Topics: Accidental Falls; Animals; Antipsychotic Agents; Clozapine; Cues; Disease Models, Animal; Dopamine; Dopamine Agents; Female; Gait Disorders, Neurologic; Interneurons; Male; Neostriatum; Observer Variation; Parasympathetic Nervous System; Parkinsonian Disorders; Rats

PD is a common neurodegenerative disease primarily affecting the cortico-basal ganglia loop.. To investigate whether chemogenetic-mediated neuromodulation of various nuclei and pathways can counterbalance basal ganglia network abnormalities and improve motor disability in experimental PD.. Experimental PD was induced by stereotactic injection of 6-OHDA to the medial forebrain bundle. Designer receptors exclusively activated by designer drugs were expressed in different basal ganglia nuclei by stereotactic injections of adeno-associated viral vectors. We compared motor performance, monitored by the open-field and rotarod tests, after random and blinded application of either normal saline or the synthetic receptor activator, clozapine-N-oxide.. Motor performance, as measured by movement velocity, rotations, and rotarod scores, were significantly improved in PD mice by enhancing the activity of the GPe with Gq custom receptors and by reducing basal ganglia output activity, targeting the output nuclei GPi and SNr with Gi custom receptors.. Our findings support the hypothesis that enhanced inhibitory output activity of the basal ganglia complex underlie motor signs in PD, and point to the therapeutic potential of chemogenetic based treatments in PD patients. © 2018 International Parkinson and Movement Disorder Society.

Topics: Animals; Basal Ganglia; Clozapine; Genetic Vectors; Male; Medial Forebrain Bundle; Mice; Motor Activity; Neurons; Oxidopamine; Parkinsonian Disorders; Rotarod Performance Test

Transplantation of DA neurons is actively pursued as a restorative therapy in Parkinson's disease (PD). Pioneering clinical trials using transplants of fetal DA neuroblasts have given promising results, although a number of patients have developed graft-induced dyskinesias (GIDs), and the mechanism underlying this troublesome side effect is still unknown. Here we have used a new model where the activity of the transplanted DA neurons can be selectively modulated using a bimodal chemogenetic (DREADD) approach, allowing either enhancement or reduction of the therapeutic effect. We show that exclusive activation of a cAMP-linked (Gs-coupled) DREADD or serotonin 5-HT6 receptor, located on the grafted DA neurons, is sufficient to induce GIDs. These findings establish a mechanistic link between the 5-HT6 receptor, intracellular cAMP, and GIDs in transplanted PD patients. This effect is thought to be mediated through counteraction of the D2 autoreceptor feedback inhibition, resulting in a dysplastic DA release from the transplant.

Topics: Animals; Clozapine; Cyclic AMP; Diterpenes; Diterpenes, Clerodane; Dopamine; Dopaminergic Neurons; Dyskinesia, Drug-Induced; Ethylamines; Female; Fetal Tissue Transplantation; Gene Knock-In Techniques; Humans; Indoles; Oxidopamine; Parkinsonian Disorders; Postoperative Complications; Rats; Receptors, Serotonin

Movement abnormalities are frequently reported in children with 22q11.2 deletion syndrome (22q11.2DS), but knowledge in this area is scarce in the increasing adult population. We report on five individuals illustrative of movement disorders and other motor abnormalities in adults with 22q11.2DS. In addition to an increased susceptibility to neuropsychiatric disorders, seizures, and early-onset Parkinson disease, the underlying brain dysfunction associated with 22q11.2DS may give rise to an increased vulnerability to multiple movement abnormalities, including those influenced by medications. Movement abnormalities may also be secondary to treatable endocrine diseases and congenital musculoskeletal abnormalities. We propose that movement abnormalities may be common in adults with 22q11.2DS and discuss the implications and challenges important to clinical practice.

Topics: Adult; Clozapine; Diagnosis, Differential; DiGeorge Syndrome; Female; Humans; Male; Middle Aged; Movement Disorders; Myoclonus; Parkinsonian Disorders; Patellar Dislocation; Phenotype; Spinal Cord Compression; Tremor; Young Adult

Direct lineage reprogramming through genetic-based strategies enables the conversion of differentiated somatic cells into functional neurons and distinct neuronal subtypes. Induced dopaminergic (iDA) neurons can be generated by direct conversion of skin fibroblasts; however, their in vivo phenotypic and functional properties remain incompletely understood, leaving their impact on Parkinson's disease (PD) cell therapy and modeling uncertain. Here, we determined that iDA neurons retain a transgene-independent stable phenotype in culture and in animal models. Furthermore, transplanted iDA neurons functionally integrated into host neuronal tissue, exhibiting electrically excitable membranes, synaptic currents, dopamine release, and substantial reduction of motor symptoms in a PD animal model. Neuronal cell replacement approaches will benefit from a system that allows the activity of transplanted neurons to be controlled remotely and enables modulation depending on the physiological needs of the recipient; therefore, we adapted a DREADD (designer receptor exclusively activated by designer drug) technology for remote and real-time control of grafted iDA neuronal activity in living animals. Remote DREADD-dependent iDA neuron activation markedly enhanced the beneficial effects in transplanted PD animals. These data suggest that iDA neurons have therapeutic potential as a cell replacement approach for PD and highlight the applicability of pharmacogenetics for enhancing cellular signaling in reprogrammed cell-based approaches.

Topics: Animals; Brain; Cell Transdifferentiation; Clozapine; Designer Drugs; Disease Models, Animal; Dopamine; Dopaminergic Neurons; Electrophysiological Phenomena; Female; Humans; Male; Mice; Mice, Knockout; Parkinsonian Disorders; Rats; Rats, Transgenic

No safe, tolerated, and effective treatment for Parkinson's disease psychosis (PDP) is available; however, clozapine and quetiapine are often used off-label. An ideal PDP drug should have a therapeutic window that alleviates psychotic symptoms at doses that allow for maintained motor control and do not cause sedation. The present study determined the effective doses of quetiapine, clozapine, and the nondopaminergic, selective 5-HT2A inverse agonist/antagonist, pimavanserin, in an animal model of PDP and compared them with the doses that caused dopamine blockade and sedation. Augmented amphetamine-induced locomotion in rats with bilateral substantia nigra lesions was used to assess antipsychotic efficacy, whereas blockade of apomorphine-induced rotations in rats with unilateral 6-hydroxydopamine lesions was used to assess antidopaminergic action and reduction in spontaneous locomotion was used to assess sedation. The estimated therapeutic ratios for clozapine and quetiapine varied between 0.81 and 3.3. In contrast, the estimated therapeutic ratios for pimavanserin were at or above 170. These results suggest that a selective 5-HT2A inverse agonist/antagonist, such as pimavanserin, may provide distinct advantages compared with clozapine or quetiapine as a therapy for PDP.

Topics: Amphetamine; Animals; Antiparkinson Agents; Antipsychotic Agents; Apomorphine; Clozapine; Dopamine; Dose-Response Relationship, Drug; Male; Parkinsonian Disorders; Piperidines; Psychotic Disorders; Quetiapine Fumarate; Rats; Rats, Sprague-Dawley; Urea

The long-term evolution of neuroleptic-induced extrapyramidal syndromes (EPS) of Parkinsonism, akathisia and tardive dyskinesia (TD) is still a controversial issue worth exploring.. A total of 200 inpatients on regular typical neuroleptics (NL) and/or clozapine were assessed in 1995 with regard to the prevalence of EPS. Altogether, 83 patients could be reassessed in 2003/04 (63 had died) using the same methods. Strict definitions of EPS were used. The complete account of NL therapy the patients were prescribed between 1995 and 2003/04 (including atypical NL other than clozapine) was considered.. The prevalences found in 1995 and 2003/04 were 17% and 29% for Parkinsonism, 14% and 14% for akathisia, and 24% and 13% for TD. There were considerable intra-individual fluctuations in EPS occurrence even when the overall prevalence rate remained the same. In intra-individual comparisons of EPS ratings on both assessments, there was a tendency for worsening of Parkinsonism to be associated with a current (2003/04) therapy with typical NL; worsening of akathisia was associated with a current therapy with atypical NL other than clozapine, amelioration of akathisia with a current therapy with clozapine; and, basically, there were no significant associations found between the changes in TD ratings and the long-term therapy with typical NL, clozapine, and other atypical NL, considering cumulative doses of all these drugs. In a multivariate analysis, there was a tendency for the long-term evolution of TD to depend on illness duration as the only variable.. There are intra-individual fluctuations in all EPS over longer time periods. The choice of current NL therapy has an impact on Parkinsonism and akathisia. The long-term evolution of TD appears independent of NL prescriptions.

Topics: Adult; Akathisia, Drug-Induced; Antipsychotic Agents; Basal Ganglia Diseases; Clozapine; Dyskinesias; Female; Follow-Up Studies; Hospitalization; Humans; Longitudinal Studies; Male; Middle Aged; Neurologic Examination; Parkinsonian Disorders; Patient Dropouts; Prevalence; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology

The present cross-sectional study examined the relationships of psychopathology, side effects, and sociodemographic factors with treatment outcomes in terms of patients' quality of life (QOL), functioning, and needs for care.. Sixty outpatients with chronic schizophrenia who had been treated with either clozapine or olanzapine for at least 6 months were investigated.. Most psychopathological symptoms as well as psychic side effects, weight gain, and female sex were associated with lower QOL, while cognitive symptoms correlated with better QOL. Female sex, cognitive symptoms, and parkinsonism negatively influenced occupational functioning, and negative symptoms determined a lesser likelihood of living independently. Age, education, depression/anxiety, negative symptoms, and psychic side effects were predictors of patients' needs for care.. Our results highlight the complex nature of patient outcomes in schizophrenia. They reemphasize the need of targeting effectiveness, i.e. both symptomatic improvement as well as drug safety, in such patients.

Topics: Adult; Age Factors; Antipsychotic Agents; Anxiety Disorders; Benzodiazepines; Clozapine; Cognition; Comorbidity; Cross-Sectional Studies; Depressive Disorder; Educational Status; Female; Humans; Male; Olanzapine; Parkinsonian Disorders; Quality of Life; Schizophrenia; Schizophrenic Psychology; Sex Factors; Socioeconomic Factors; Treatment Outcome; Weight Gain

Clozapine is the least likely anti-psychotic to induce extrapyramidal symptoms (EPS). We present a surprising case of a woman schizophrenic patient treated with clozapine suffering from EPS. Single photon emission computed tomography (SPECT) revealed a low density of presynaptic dopamine transporters in our patient's brain. A comorbid diagnosis of Parkinson's disease in schizophrenia was confirmed in this way. This helped us to find a proper therapeutic strategy for our patient.

Topics: Antipsychotic Agents; Brain; Clozapine; Diagnosis, Differential; Female; Humans; Middle Aged; Parkinson Disease, Secondary; Parkinsonian Disorders; Recurrence; Schizophrenia; Schizophrenic Psychology; Tomography, Emission-Computed, Single-Photon

Regulation of dopamine D2 receptor (D2) function plays an important role in alleviating either the motor deficits of Parkinson's disease or psychotic symptoms of schizophrenia. D2 also plays a critical role in sensorimotor gating which can be measured by monitoring the prepulse inhibition of the startle response. Alternative splicing of the D2 gene generates two isoforms, D2S and D2L. Here we investigated the role of D2S and D2L in the mechanisms of action of dopaminergic drugs, using mice lacking D2L (D2L(-/-)) but expressing D2S as a model system. We found that the typical antipsychotic raclopride was much less potent in inhibiting locomotor activity and eliciting catalepsy (or parkinsonism) in D2L(-/-) mice, whereas the atypical antipsychotic clozapine was equally effective in D2L(-/-) and wild-type mice. These suggest that the deletion of D2L diminishes drug-induced parkinsonism. Furthermore, two dopamine agonists, amphetamine and apomorphine, reduced prepulse inhibition to a similar degree in D2L(-/-) and wild-type mice. These results together suggest that D2S alone can mediate the action of clozapine and the dopamine agonist-induced disruption of prepulse inhibition. The differential binding affinities of these agents for D2S vs D2L were not sufficient to explain the divergent effects of typical vs atypical antipsychotics in D2L(-/-) mice. These findings suggest that D2S and D2L may differentially contribute to the therapeutic actions and side effects of antipsychotic agents, and may have implications for developing better antipsychotic agents.

Topics: Amphetamine; Animals; Antipsychotic Agents; Apomorphine; Clozapine; Dopamine Agonists; Dose-Response Relationship, Drug; Hallucinogens; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Parkinsonian Disorders; Protein Isoforms; Raclopride; Receptors, Dopamine D2

Clozapine reduces L-3,4-dihydroxyphenylalanine (L-Dopa)-induced dyskinesias in parkinsonian patients. To test if the antidyskinetic effect of clozapine is related to antagonism at the dopamine D(4) receptor, we investigated the effect of 8-methyl-6-(4-methyl-1-piperazinyl)-11H-pyrido[2,3-b][1, 4]benzodiazepine (JL-18), a structural analog of clozapine which is more selective for this receptor. Four 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP)-treated cynomolgus monkeys with a stable parkinsonian syndrome and reproducible dyskinesias to L-Dopa were used in this study. They were injected subcutaneously (s.c.) with L-Dopa methyl ester (125 mg per animal) plus benserazide (50 mg per animal; L-Dopa/benserazide) alone or in combination with JL-18 (at the doses of 0.1, 0.3, or 0.9 mg/kg, s.c.). Subcutaneous injection of sterile saline was used as control. L-Dopa/benserazide increased locomotion and improved parkinsonism but also induced dyskinesias. Co-administration of JL-18, at low doses (0.1, 0.3 mg/kg) with L-Dopa/benserazide, produced a dose-dependent reduction in L-Dopa-induced dyskinesias without a parallel return to parkinsonism. The present results suggest that novel selective dopamine D(4) receptor antagonists may represent a useful tool to reduce L-Dopa-induced dyskinesias.

Topics: Analysis of Variance; Animals; Antiparkinson Agents; Behavior, Animal; Benserazide; Clozapine; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Female; Levodopa; Macaca fascicularis; Motor Activity; Parkinsonian Disorders