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Schizophrenia treatments.

Schizophrenia is a chronic psychiatric illness that causes devastating mental and social impairment in a patient's life. The worldwide prevalence of schizophrenia is approximately 1%, with equal rates occurring in both men and women. However, it is the fourth-leading cause of disability in adults.

Initially described as "dementia praecox" in the late 1800s, the diagnosis of schizophrenia typically occurs in the early 20s. Patients experience a constellation of symptoms, including hallucinations, delusions, mood changes, disorganized behavior and cognitive impairment. Although researchers have postulated a number of risk factors for the etiology of schizophrenia--family history, environmental and developmental factors--the main theory centers on hyperdopaminergic activity in the mesolimbic pathway of the brain. This pathophysiological description of schizophrenia is based on the mechanism of action of antipsychotics, which work by antagonizing post-synaptic dopamine receptors.

The diagnosis of schizophrenia includes two or more of the following: positive symptoms, disorganized speech, disorganized or catatonic behavior, and negative symptoms. Positive symptoms include delusions, hallucinations and paranoia, while negative symptoms include affect flatting (lack of emotion), alogia (lack of speech), anhedonia (lack of pleasure) and avolition (lack of motivation). For the patient to meet the diagnosis, one of the two symptoms must be delusions, hallucinations or disorganized speech. Symptoms must also be continuously present for at least six months, with active symptoms for at least one month.

The presentation of schizophrenia must not be due to another psychiatric-, medical- or substance-induced cause. Delusions are defined as fixed false beliefs maintained despite convincing evidence otherwise, and hallucinations are usually auditory and visual, rarely gustatory, tactile or olfactory. Patients diagnosed with schizophrenia will experience these symptoms throughout their life with varying degrees of severity and will have significant social impairment from them.

The first antipsychotic, initially called a "neuroleptic," was used in the 1950s. Since then, numerous other antipsychotics have been developed and prescribed in the treatment of schizophrenia. Antipsychotics are divided into two main groups: first-generation or typical antipsychotics, and second-generation or atypical antipsychotics. Although the atypical antipsychotics are recommended as first-line treatment for schizophrenia, the typical antipsychotics have demonstrated comparable efficacy for the positive symptoms of schizophrenia and are still widely prescribed.

The negative symptoms and cognitive impairment of schizophrenia are more difficult to treat and are less responsive to both typical and atypical antipsychotics. Clozapine (Clozaril) is the only antipsychotic reported to be effective in treatment-resistant patients with schizophrenia and is usually reserved for patients who have failed multiple trials with other agents.

Four new atypical antipsychotics were developed in the past five years, including paliperidone (Invega), asenapine (Saphris), iloperidone (Fanapt) and lurasidone (Latuda). These four new agents are similar in efficacy and tolerability to the existing atypical antipsychotics.

Therefore, an antipsychotic is most often chosen based on its side-effect profile.

Typical antipsychotics are associated with causing more extrapyramidal side effects. Extrapyramidal side effects include early onset dyskinesias, such as dystonias (twisting of the neck or facial spasms); akathisia (inner restlessness with inability to sit still); and Parkinsonian symptoms (bradykinesia, pill-rolling tremor or shuffling gait); and late onset dyskinesias, such as tardive dyskinesia (irregular jerking movements of the face and extremities) and dystonia.

Early onset dyskinesias respond well to a reduction in dose or a discontinuation of the antipsychotic or concomitant treatment with an anticholinergic medication or a benzodiazepine. Tardive dyskinesia and dystonia can be irreversible if allowed to persist without discontinuing the offending antipsychotic.

Other side effects include an increase in prolactin levels, sexual dysfunction, neurlopetic malignant syndrome (NMS) and QTc prolongation. All typical antipsychotics are pregnancy category C.

Atypical antipsychotics are associated with causing metabolic side effects, including weight gain, increases in low-density lipoprotein (LDL) and triglycerides, type 2 diabetes, and an increase in waist circumference and blood pressure. There are very few treatment options for minimizing or reversing these metabolic effects.

Providers most often will use atypical antipsychotics with a lower risk for metabolic changes. These include aripiprazole (Abilify), ziprasidone (Geodon) and lurasidone (Latuda). Clozapine and olanzapine (Zyprexa) are categorized as the highest risk, while all other antipsychotics are considered moderate risk.

Regardless of the risk conferred, all patients started on an atypical antipsychotic should, at the very least, have a family history, blood pressure, waist circumference, fasting lipid panel and a body mass index performed at baseline and yearly.

Other side effects from the atypical antipsychotics include sedation, orthostatic hypotension, QTc prolongation and anticholinergic side effects (dry mouth, blurred vision, constipation and urinary incontinence). Clozapine can cause agranulocytosis and requires a white blood cell count and an absolute neutrophil count weekly for the first six months of treatment, every other week for the next six months of treatment and then once monthly for duration of treatment. All atypical antipsychotics are pregnancy category C, except clozapine and lurasidone, which are pregnancy category B.

Goals of antipsychotic treatment include reducing symptomatology, preventing or delaying a relapse, improving the quality of life, reducing social impairment, minimizing side effects of medications and preventing suicide. Early symptoms that improve rapidly following initiation of treatment include insomnia, hostility, hallucinations and poor self-care. Delusions, paranoia, negative symptoms, cognitive impairment and social impairment may be slower to remit.

Because schizophrenia is a chronic disorder and patients will develop comorbid medical and psychiatric illnesses, it is important to look for drug-induced disorders and drug-drug interactions. There are different formulations of many antipsychotics available, including short--and long-acting injectables, oral solutions and orally disintegrating tablets.

Recently, the Food and Drug Ad ministration approved an inhaled power formulation of loxapine (Adasuve) for the treatment of agitation in bipolar disorder and schizophrenia. Long-acting injectable antipsychotics or depots may help improve adherence to antipsychotic treatment for patients with schizophrenia who struggle with compliance to daily regimens.

Andrew Muzyk, Pharm.D., is an assistant professor at the Campbell University College of Pharmacy and Health Sciences in Buies Creek, N.C.; practices as a clinical pharmacist at Duke University Hospital in Durham, N.C.; and specializes in the practice of internal medicine and psychiatry.
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Title Annotation:Focus
Author:Muzyk, Andrew
Publication:Chain Drug Review
Date:Jul 7, 2014
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