Snapshot A 23-year-old male is brought into the inpatient psychiatric hospital after a suicide attempt. When talking with the patient he seemed to be responding to internal stimuli at times. He states that he heard voices telling him to kill himself. He said he has heard these voices for over a year now but within the past month they have become louder, more persistent and convincing. Overview 2 classes typical older stronger D2 receptor antagonism ↑ [cAMP] atypical newer weaker D2 receptor antagonism and stronger 5-HT2, α, and H1 antagonism Targets dopaminergic neurons specific pathways affected include: nigrostriatal (extrapyramidal motor) mesolimbic (mood and reward) tuberoinfundibular (prolactin release) Typical Antipsychotics Overview Typical Antipsychotics High Potency Antipsychotics (in Descending Order) Advantages Disadvantages Unique Features Haloperidol Fewer side effects of sedation and hypotension High association with extrapyramidal symptoms Able to use as long-acting depot injections Can be given IM in acute situations Fluphenazine Perphenazine Chlorpromazine Lower frequency of extrapyramidal side effects Greater incidence of anticholinergic side-effects, hypotension, sedation Corneal deposits Thioridazine Retinal deposits QT prolongation Introduction Overview also known as neuroleptics highly fat soluble results in storage for long time in body fat Drugs ("haloperidol + -azines") high potency - low dose needed haloperidol trifluoperazine fluphenazine low potency - high dose needed thioridazine chlorpromazine Clinical use schizophrenia primarily positive symptoms psychosis acute mania temporary treatment because lithium has slow onset Tourette's syndrome Toxicity high potency ↑ extrapyramidal system (EPS) side effects due to high affinity for D2 receptor has characteristic time course early onset/reversible symptoms 4 hours = acute dystonia spasm of face, neck, tongue, extraocular muscles treat with benztropine or diphenhydramine 4 days = Parkinsonism muscle rigidity, ankinesia, tremor, shuffling gait 4 days to 4 weeks = akathisia urge to move late onset/irreversible symptoms 4 months = tardive dyskinesia involuntary, repetitive movements of facial, tongue, neck muscles anticholinergics worsen! must reduce dose or switch to an atypical antipsychotic ↓ non-specific side effects fluphenazine has been implicated in causing hypothermia in select cases low potency ↓ EPS side effects ↑ non-specific side effects due to low affinity to D2 receptors and high concentrations needed to achieve effect muscarinic receptor antagonism dry mouth and constipation vision problems α receptor antagonism orthostatic hypotension sexual dysfunction histamine receptor antagonism sedation chlorpromazine can cause corneal deposits thioridazine can cause retinal deposits endocrine side effects dopamine normally inhibits prolactin secretion antagonism of receptor may result in hyperprolactinemia can cause galactorrhea neuroleptic malignant syndrome (NMS) presentation high fever, hypertension, tachycardia, “lead pipe” rigidity, elevated CPK, leukocytosis, metabolic acidosis treatment discontinue offending agent use of muscle relaxant (e.g., dantrolene) Side Effects of High Potency Antipsychotics Extrapyramidal Side Effects of High Potency D2 Blockers (Haloperidol, Fluphenazine, Perphenazine) 3 Hours: Acute Dystonia 3 Days - Weeks: Bradykinesia (Pseudo-Parkinsonism) 3 Months: Akathisia 3 Years: Tardive Dyskinesia Emergency: Neuroleptic Malignant Syndrome Muscle spams (neck, eye, diffuse) Trouble swallowing Symptoms of Parkinson's disease: tremors, bradykinesia, rigidity Sustained feeling of motion/restlessness Uncontrollable repetitive, stereotypical writhing movements, usually of the tongue High fever Muscle rigidity Unstable vitals Increased CK, K+, and WBC's Treatment of Side Effects Anticholinergic medications:(benztropine, diphenhydramine, trihexyphenidyl) β-blockers Benzodiazepines Stop high potency D2 blockers Switch to atypicals Stop antipsychotic IV fluids Cooling Dantrolene NOTE: You can always decrease the dose or switch to a different antipsychotic – choose the drug with the side-effect profile that the patient can tolerate. Atypical Antipsychotics Overview Atypical Antipsychotics Medication Unique features and side effects Risperidone High potency Usually first line Hyperprolactinemia Weight gain Olanzapine Severe weight gain Very sedating Ziprasidone Minimal to no weight gain Increased QTc Quetiapine Low potency Sedating Weight gain Useful in bipolar depression and augmentation of major depression therapy Lurasidone Minimal weight gain Useful in biploar depression Clozapine Weight gain Most effective anti-psychotic Decreased suicide risk Agranulocytosis Myocarditis Sialorrhea Orthostatic hypotension Increased seizures Aripiprazole D2 partial agonist Augmentation of major depression therapy Introduction Drugs olanzapine clozapine quetiapine risperidone aripiprazole ziprasidone Mechanism antagonist at 5-HT2, α, H1, and dopamine receptors Clinical use schizophrenia both positive and negative symptoms olanzapine OCD anxiety disorder depression mania Tourette's syndrome Toxicity less EPS and anticholinergic side effects as compared to traditional antipsychotics olanzipine weight gain clozapine agranulocytosis requires patients to have weekly WBC monitoring treat with drug cessation, neutropenic protocol, possibily filgrastim weight gain ziprasidone prolonged QT and possible resultant torsades risperidone EPS