Antipsychotics Overview

• All conventional and atypical antipsychotics have approximately equal efficacy, with the notable exception of clozapine which is unique for its efficacy in treatment refractory schizophrenia (but is reserved for after other drugs have failed, due to its significant toxicities – see below).  The main advantage of atypical antipsychotics is the lower rates of extrapyramidal side effects and tardive dyskinesia.

A.  Conventional (or Typical) Antipsychotics

• Good efficacy, but are associated with significant Parkinsonian extrapyramidal side effects (rigidity, bradykinesia, tremor, akathisia), and a 5-7% cumulative risk/year of Tardive Dyskinesia.
• Unlike Atypical antipsychotics, these also come in IV formulations which are useful in many inpatient settings.
• Low potency Antipsychotics (e.g. Chlorpormazine) – strong sedating effect, anticholinergic effect, and more likely to cause EPS
• High potency Antipsychotics (Haloperidol, Fluphenazine) – less sedating, anticholingeric, and less likely to cause EPS

B.  Atypical Antipsychotics

• As a whole, are associated with a lower risk of EPS and tardive dyskinesia (<1% cumulative risk/year) as compared to conventional antipsychotics.  However, this does not mean that they don’t have significant side effects – they are associated with significant metabolic abnormalities, weight gain, etc. (see below).
• Atypical antipsychotics include Risperidone, Olanzapine, Quetiapine, Ziprasidone, and Clozapine.
• Clozapine, as mentioned, is unique for its efficacy in treatment-resistant schizophrenia: among the 30% of schizophrenic patients who do not respond to other antipsychotics, 30-50% will respond to clozapine.  It is usually tried after 2-4 other drugs have failed.  Main reason for the reluctance to use it despite its efficacy is its side effects, namely Agranulocytosis which can be life-threatening.  This occurs in 1-2% of patients during the first 6 months and less frequently afterwards; weekly CBCs are required in the first 6 months and slightly less frequently thereafter.  Other side effects: Orthostatic hypotension (this is often the limiting factor in dose uptitration), Tachycardia, Weight gain and metabolic syndrome, Sedation, Seizures, and also drug fever.  However, with drug fever, it is always important to exclude agranulocytosis with concomitant infection.

Summary of Side Effects Associated with Antipsychotics:
1. Tardive Dyskinesia – late onset of choreoathetotic movements.  Risk factors include the use of conventional antipsychotics over atypical, long duration of use, and older age.  Although it is usually thought of as a chronic and progressive disease, it actually can have a variable course and improve with discontinuation of the offending med.
2.  Extrapyramidal Symptoms – again, more with conventional antipsychotics.   Sometimes responds to dose reduction or switching another medication.  Benzotropine and Benadryl can be tried for symptom relief.
3.  Akathisia – subjective sense of restlessness often with voluntary movements of the trunk and limbs.  Can be very distressing to the patients.  More common with conventional antipsychotics.  Can treat with beta blockers, benzos, anticholinergics, antihistamines.
4.  Metabolic Side effects (Diabetes, Hyperlipidemia, Hypertension, Weight Gain) – more common with the atypical antipsychotics, especially Clozapine.
5.  Neuroleptic Malignant Syndrome – can be a life-threatening disease that occurs with all antipsychotics, but most often with the conventional, high-potency drugs (haloperidol, fluphenazine).  Classically, presents with a tetrad of symptoms: Fever (often high grade, > 40 degrees), Rigidity (associated with marked elevations in CK), Altered mental status, and Autonomic instability.  Not all of these symptoms will present at the same time, and interestingly CK can sometimes be normal early on, especially before onset of rigidity.  Other lab abnormalities include leukocytosis and elevated LFTs.  Treatment involves stopping the med (obviously), supportive care with IVFs, cardiac monitoring, electrolyte repletion, etc.  Also, Dantrolene has some efficacy in mitigating the course of disease. 
6.  Increased risk of Sudden Cardiac Death – both typical and atypical antipsychotics increase the risk of sudden cardiac death by about twofold from baseline.  The mechanism is not entirely clear but is thought to be due to effects on cardiac repolarization and QT prolongation. 

(Chanu Rhee MD, 4/21/11)