These include the first-generation (typical) neuroleptics, which act by blocking dopamine D2 receptors, and the second-generation (atypical) neuroleptics, which act on dopamine, serotonin, and other neurotransmitter systems. Some antipsychotic effect may occur within hours or days of initiating treatment, but full effects usually require 6 weeks to several months of daily, therapeutic dosing.
First-Generation Antipsychotics 
Useful to group into high-, mid-, and low-potency neuroleptics (Table 200-3 Antipsychotic Agents). High-potency neuroleptics are least sedating, have almost no anticholinergic side effects, and have a strong tendency to induce extrapyramidal side effects (EPSEs). The EPSEs occur within several hours to several weeks of beginning treatment and include acute dystonias, akathisia, and pseudo-parkinsonism. Extrapyramidal symptoms respond well to trihexyphenidyl, 2 mg twice daily, or benztropine mesylate, 1-2 mg twice daily. Akathisia may respond to beta blockers. Low-potency neuroleptics are very sedating, may cause orthostatic hypotension, are anticholinergic, and tend not to induce EPSEs frequently.
Up to 20% of pts treated with conventional antipsychotic agents for >1 year develop tardive dyskinesia (probably due to dopamine receptor supersensitivity), an abnormal involuntary movement disorder most often observed in the face and distal extremities. Treatment includes gradual withdrawal of the neuroleptic, with possible switch to a novel neuroleptic; anticholinergic agents can worsen the disorder. Valbenazine, a vesicular monoamine transporter 2 inhibitor that depletes presynaptic dopamine, has recently received FDA approval for treatment of tardive dyskinesia.
Rarely, pts exposed to neuroleptics develop neuroleptic malignant syndrome (NMS), a life-threatening complication with a mortality rate as high as 25%; hyperpyrexia, autonomic hyperactivity, muscle rigidity, obtundation, and agitation are characteristics associated with increased WBC, increased creatine phosphokinase, and myoglobinuria. Treatment involves immediate discontinuation of neuroleptics, supportive care, and use of dantrolene and bromocriptine.
Second-Generation Antipsychotics
A class of agents that has become the first line of treatment (Table 200-3 Antipsychotic Agents); efficacious in treatment-resistant pts, tend not to induce EPSEs or tardive dyskinesia, and appear to have uniquely beneficial properties on negative symptoms and cognitive dysfunction. Main problem is side effect of weight gain (most prominent with clozapine and in olanzapine; can induce diabetes). The CATIE study, a large-scale investigation of antipsychotic agents in the “real world,” revealed a high rate of discontinuation of all medications over 18 months; olanzapine was modestly more effective than other agents but with a higher discontinuation rate due to side effects.