University of Nizwa College of Pharmacy and Nursing School of Pharmacy PHARMACOTHERAPY - I PHCY 310 Lecture -12 Psychiatric Disorders “Schizophrenia” Dr. Sabin Thomas, M. Pharm. Ph. D. Assistant Professor in Pharmacy Practice School of Pharmacy University of Nizwa

Course Outcome Upon completion of this lecture the students will be able to Describe pathophysiology, diagnosis, and therapeutic choices including non-pharmacologic and pharmacologic treatments for schizophrenia, Explain the different phases of treatment in schizophrenia.

Psychosis is brain disorder in which there is loss of contact with reality, affecting the ability to think, feel, perceive and act. Investigations 1- History - Withdrawal from usual activities with friends and family - Rapid fluctuations in mood (emotional lability) - Unreasonable suspiciousness - Unusual or bizarre behavior - Hallucinations - Difficulties in thinking or expressing thoughts 2- Clinical rating scales to monitor the psychotic event - Clinical Global Impression Scales for Severity (CGI-S) - Clinical Global Impression Scales for Change (CGI-C) - Global Assessment of Functioning (GAF)

Pathophysiology Schizophrenia is usually a lifelong psychiatric disability. Psychosis may result from hyper- or hypo activity of dopaminergic processes in specific brain regions. This may include the presence of a dopamine (DA) receptor defect. Schizophrenic patients with abnormal brain scans have higher whole blood 5-HT concentrations, and these concentrations correlate with increased ventricular size. Clinical presentation Symptoms of the acute episode may include the following: being out of touch with reality; hallucinations (especially hearing voices); delusions (fixed false beliefs); ideas of influence (actions controlled by external influences); disconnected thought processes (loose associations); ambivalence (contradictory thoughts); flat, inappropriate, or labile affect; autism (withdrawn and inwardly directed thinking); uncooperativeness, hostility, and verbal or physical aggression; impaired self-care skills; and disturbed sleep and appetite.

Therapeutic Choices Nonpharmacologic Choices - Medication adherence - Family psychoeducation - Assessment of postpsychotic depression and suicidality Pharmacologic Choices There are two major classes of antipsychotics:Selection of an antipsychotic should be based on (1) the need to avoid certain side effects, (2) concurrent medical or psychiatric disorders, and (3) patient or family history of response. First-generation (typical) antipsychotics (FGAs): e.g., fluphenazine, trifluoperazine, chlorpromazine, haloperidol, and pimozide. Second-generation (atypical) antipsychotics (SGAs): e.g., aripiprazole, clozapine, olanzapine, quetiapine, risperidone, ziprasidone, and paliperidone. Paliperidone is the active metabolite of risperidone, and it is not metabolized by the liver. Therefore it has less drug-drug interactions compared to other antipsychotics.

INITIAL THERAPY The goals during the first 7 days are decreased agitation, hostility, anxiety, and aggression and normalization of sleep and eating patterns. In general, titrate over the first few days to an average effective dose. After 1 week at a stable dose, a modest dosage increase may be considered. If there is no improvement within 3 to 4 weeks at therapeutic doses, then an alternative antipsychotic should be considered. IM antipsychotic administration (e.g., ziprasidone 10 to 20 mg, olanzapine 2.5 to 10 mg, or haloperidol 2 to 5 mg) can be used to calm agitated patients. Intramuscular (IM) lorazepam, 2 mg, as needed in combination with the maintenance antipsychotic may actually be more effective in controlling agitation than using additional doses of the antipsychotic.

STABILIZATION THERAPY During weeks 2 and 3, the goals should be to improve socialization, selfcare habits, and mood. Improvement in formal thought disorder may require an additional 6 to 8 weeks. Most patients require a dose of 300 to 1,000 mg of CPZ equivalents (of FGAs) daily or SGAs in usual labeled doses. Dose titration may continue every 1 to 2 weeks as long as the patient has no side effects. If symptom improvement is not satisfactory after 8 to 12 weeks, a different strategy should be tried.

MAINTENANCE THERAPY Medication should be continued for at least 12 months after remission of the first psychotic episode. Continuous treatment is necessary in most patients at the lowest effective dose. Antipsychotics (especially FGAs and clozapine) should be tapered slowly before discontinuation to avoid rebound cholinergic withdrawal symptoms.

If partial or poor adherence is an issue, a long-acting or depot injectable antipsychotic should be considered (e.g., risperidone microspheres, haloperidol decanoate, fluphenazine decanoate). Only clozapine has shown superiority over other antipsychotics for the management of treatment-resistant schizophrenia. Propranolol, pindolol, and nadolol have been used for antiaggressive effects. ADVERSE EFFECTS Autonomic Nervous System: Anticholinergic (ACh) side effects include impaired memory, dry mouth, constipation, tachycardia, blurred vision, inhibition of ejaculation, and urinary retention.

Central Nervous System Extrapyramidal System Dystonias are prolonged tonic muscle contractions, with rapid onset (usually within 24 to 96 hours of dosage initiation); they may be life threatening (e.g., pharyngeal-laryngeal dystonias). Pseudoparkinsonism akinesia, bradykinesia, tremor, rigidity, postural abnormalities Tardive Dyskinesia abnormal involuntary movements Sedation and Cognition Seizures Thermoregulation Hyperpyrexia can lead to heat stroke

Neuroleptic Malignant Syndrome Symptoms develop rapidly over 24 to 72 hours and include body temperature exceeding 38°C (100.4°F), altered level of consciousness, autonomic dysfunction (tachycardia, labile blood pressure, diaphoresis, tachypnea, urinary or fecal incontinence), and rigidity. Laboratory evaluation frequently shows leukocytosis, increases in creatine kinase (CK), aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), and myoglobinuria.