clozapine and Central-Nervous-System-Diseases

Clozapine treatment remains the gold standard for treatment-resistant schizophrenia, but treatment with clozapine is associated with several side-effects that complicate the use of the drug. This clinical overview aims to provide psychiatrists with knowledge about how to optimize clozapine treatment. Relevant strategies for reducing side-effects and increasing the likelihood of response are discussed.. Studies of clozapine available in MEDLINE were reviewed.. A slow up-titration of clozapine is recommended in order to reach the optimal dosage of clozapine and diminish the risk of dose-dependent side-effects. Particularly, in case of partial response or non-response, the use of therapeutic drug monitoring of clozapine is recommended. Plasma levels above the therapeutic threshold of 350-420 ng/ml are necessary to determine non-response to clozapine. To ease the burden of dose-dependent side-effects, dose reduction of clozapine should be tried and combination with another antipsychotic drug may facilitate further dose reduction. For most side-effects, counteracting medication exists. Augmentation with lamotrigine, antipsychotics, or electroconvulsive therapy may be beneficial in case of partial response to clozapine.. Treatment with clozapine should be optimized in order to increase the rate of response and to minimize side-effects, thus diminishing the risk of discontinuation and psychotic relapse.

Topics: Antipsychotic Agents; Calcium Channel Blockers; Central Nervous System Diseases; Clozapine; Combined Modality Therapy; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Monitoring; Drug Therapy, Combination; Electroconvulsive Therapy; Heart Diseases; Humans; Lamotrigine; Schizophrenia; Treatment Outcome; Triazines

Clozapine has been found to be superior to traditional neuroleptics in the treatment of refractory schizophrenia and is increasingly being used to treat schizophrenia, affective disorders, some neurological disorders, and aggression. For many patients, clozapine offers new hope for the successful pharmacological management of a disabling mental disorder. However, up to 17 percent of patients must discontinue treatment with clozapine because of adverse effects, which also limit the rate at which the dose can be increased and the maximum dose that can be tolerated. This article reviews strategies for minimizing and managing the adverse effects of clozapine, including agranulocytosis, seizures, sedation, delirium, obsessive-compulsive symptoms, hypotension, tachycardia, weight gain, sialorrhea, elevated liver enzymes, constipation, nausea, enuresis, fever, and neuromuscular effects. Incidence and morbidity are presented first. Then, the known or hypothesized pathophysiology of the adverse effects are described. Finally, nonpharmacological and pharmacological interventions are reviewed. Under-standing the incidence, pathophysiology, and treatments of adverse effects is essential for a positive therapeutic outcome when prescribing clozapine.

Topics: Agranulocytosis; Antipsychotic Agents; Cardiovascular Diseases; Central Nervous System Diseases; Clozapine; Drug Administration Schedule; Dyskinesia, Drug-Induced; Gastrointestinal Diseases; Humans; Schizophrenia

Adverse effects of antipsychotics often lead to noncompliance. Thus, clinicians should address patients' concerns about adverse effects and attempt to choose medications that will improve their patients' quality of life as well as overall health. The side effect profiles of the atypical antipsychotics are more advantageous than those of the conventional neuroleptics. Conventional agents are associated with unwanted central nervous system effects, including extrapyramidal symptoms (EPS), tardive dyskinesia, sedation, and possible impairment of some cognitive measures, as well as cardiac effects, orthostatic hypotension, hepatic changes, anticholinergic side effects, sexual dysfunction, and weight gain. The newer atypical agents have a lower risk of EPS, but are associated in varying degrees with sedation, cardiovascular effects, anticholinergic effects, weight gain, sexual dysfunction, hepatic effects, lowered seizure threshold (primarily clozapine), and agranulocytosis (clozapine only). Since the incidence and severity of specific adverse effects differ among the various atypicals, the clinician should carefully consider which side effects are most likely to lead to the individual's dissatisfaction and noncompliance before choosing an antipsychotic for a particular patient.

Topics: Agranulocytosis; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Central Nervous System Diseases; Clozapine; Dibenzothiazepines; Drug Interactions; Dyskinesia, Drug-Induced; Health Status; Humans; Hypotension, Orthostatic; Olanzapine; Pirenzepine; Quality of Life; Quetiapine Fumarate; Receptors, Cholinergic; Risperidone; Schizophrenia; Sexual Dysfunctions, Psychological; Sleep Wake Disorders; Treatment Refusal; Weight Gain

The arrival of clozapine has been one of the most significant developments in antipsychotic drug treatment since the advent of chlorpromazine ushered in the psychopharmacologic era. However, its utilization has been significantly limited and complicated by its potential to cause adverse effects and agranulocytosis in particular. It must be emphasized that clozapine has a side effect profile that is in many ways distinct from standard typical antipsychotic drugs. Side effects with clozapine are common and range from the benign to the potentially lethal. The most common side effects include sedation, dizziness, and sialorrhea during sleep; the most serious are agranulocytosis, seizures and respiratory depression. Although side effects from clozapine are not necessarily preventable, they are for the most part manageable. Even with the most serious adverse effects, proper knowledge of the medication's actions, clinical vigilance, and prompt intervention can prevent the occurrence of significant morbidity and mortality as a consequence of clozapine treatment.

Topics: Adult; Aged; Agranulocytosis; Blood Chemical Analysis; Central Nervous System Diseases; Clozapine; Female; Humans; Male; Middle Aged; Neuroleptic Malignant Syndrome; Psychotic Disorders; Seizures

Multitargeting is a valuable concept in drug design for the development of effective drugs for the treatment of multifactorial diseases. This concept has most frequently been realized by incorporating two or more pharmacophores into a single hybrid molecule. Many such hybrids, due to the increased molecular size, exhibit unfavorable physicochemical properties leading to adverse effects and/or an inappropriate ADME (absorption, distribution, metabolism, and excretion) profile. To avoid this limitation and achieve additional therapeutic benefits, here we describe a novel multitargeting strategy based on the synergistic effects of a parent drug and its active metabolite(s). The concept of metabolism-activated multitargeting (MAMUT) is illustrated using a number of examples.

Topics: Amine Oxidase (Copper-Containing); Anti-Inflammatory Agents; Antipsychotic Agents; Cell Adhesion Molecules; Central Nervous System Diseases; Clozapine; Drug Design; Drug Synergism; Humans; Indans; Ligands; Monoamine Oxidase; Pharmaceutical Preparations; Receptor, Muscarinic M1

Previously we designed a series of pyridinic anticholinesterasic compounds based on molecular hybridization between tacrine and the natural piperidine alkaloid (-)-3-O-acetylspectaline isolated from Senna spectabilis. Based on the information that the cholinergic system has an important role in the treatment of schizophrenia and depression, we herein report the evaluation of a series of pyridinic compounds in animal models for antipsychotic and antidepressant-like activities. Compound 2 decreased the immobility time of mice in the forced swimming test (5 and 10mg/kg p.o.) and prevented the climbing behavior induced by apomorphine (10mg/kg, p.o.), without impairing animals locomotor activity.

Topics: Animals; Antidepressive Agents; Behavior, Animal; Central Nervous System Diseases; Disease Models, Animal; Mice; Piperidines; Pyridines; Schizophrenia

A 53-year-old patient suffering from delusional disorder developed an anticholinergic syndrome 19 days after initiation of paroxetine in addition to a steady dose of clozapine. The clozapine plasma concentration had doubled and was in the toxic range. On re-exposition with a lower clozapine dosage the increase was significantly lower. The importance of a dose-dependent interaction of both drugs is emphasized and a possible pharmacological explanation described. With regard to interactions of SSRIs and clozapine, fluvoxamine, a potent inhibitor of cytochrome P450 1A2, gives rise to higher clozapine levels at an earlier time, compared to other SSRIs (paroxetine, fluoxetine and sertraline), which are potent cytochrome P450 2D6 inhibitors.

Topics: Antidepressive Agents, Second-Generation; Antipsychotic Agents; Blood Pressure; Central Nervous System Diseases; Clozapine; Cytochrome P-450 CYP2D6 Inhibitors; Depressive Disorder; Drug Interactions; Drug Therapy, Combination; Dysthymic Disorder; Humans; Male; Middle Aged; Paroxetine; Selective Serotonin Reuptake Inhibitors

Clozapine, used in the treatment of patients with schizophrenia resistant to other neuroleptic medication, is metabolized by the hepatic microsomal system to demethyl-clozapine and clozapine-N-oxide. Changes in clozapine serum concentrations have been documented after initiation of therapy with medications known to induce or inhibit liver microsomal enzymes. These interactions are of clinical importance when diminished efficacy or increased toxic effects of clozapine therapy occur. A 34-year-old schizophrenic man had increased clozapine serum concentrations, leukocytosis, and adverse effects as a result of concomitant erythromycin therapy given for suspected lower respiratory tract infection. Symptoms included somnolence, difficulty in coordination and ambulation, slurred speech, disorientation, and incontinence. The symptoms resolved after treatment with clozapine and erythromycin were discontinued, and treatment with clozapine was gradually resumed.

Topics: Adult; Anti-Bacterial Agents; Antipsychotic Agents; Central Nervous System Diseases; Clozapine; Drug Synergism; Erythromycin; Humans; Male