The term ‘atypical’ was originally applied to clozapine because it was unrelated to previous antipsychotic agents chemically and in its effects in animal models . Currently, ‘atypicals’ are defined as antipsychotics with the following characteristics: greater improvement in negative symptoms over conventional agents; minimal to no risk of EPS/TD; minimal to no effect on serum prolactin levels; and minimal to no potential for provoking catalepsy in rats . Although commonly used, this term does not strictly apply to each of the second generation antipsychotics. It is thought that the greater affinity for 5-HT2 compared with D2 receptors may account for these agents’ atypicality; however, some conventional antipsychotics also share similar serotonin and dopamine binding profiles (ie, loxapine, thioridazine and chlorpromazine) . In addition, the newer compounds are a heterogeneous group with distinguishing pharmacological and clinical features. The pharmacological profiles are illustrated in Table 2, and the relevant clinical features are described in the section entitled ‘Second generation antipsy-chotics’. Table 2 can be used by clinicians to both predict and explain benefits and adverse effects by correlating their understanding of receptor functions and pharmacological effects. buy diabetes drugs
TABLE 2 In vitro receptor binding affinities of the second generation antipsychotics (Ki values-nM)
Smaller Ki values (the amount of drug required to displace binding of a ligand by 50%) indicate a greater receptor affinity and can be used both to predict and to explain the clinical and adverse effects of drug treatment with the potential for improving the rationale for therapeutic interventions. *In vitro receptor binding profile in cloned human receptors; fIn vitro receptor binding profile in animalbrain. CLZ Clozapine; EPS txtrapyramidalside effects; HUL Haloperidol; HT Hydroxytriptamine; OLZ Olanzapine; QTP Quetiapine; RSP Risperidone; ZIP Ziprasidone. Data from references 56,77
SECOND GENERATION ANTIPSYCHOTICS Clozapine
Clozapine, originally synthesized in the 1960s, was held back from the global market due to reports of agranulocytosis associated with its use in the 1970s. However, early clinical observations led to the landmark trial by Kane et al and more recent trials that demonstrated its superiority to conventional agents in the management of treatment-resistant schizophrenia. (The strict criteria of Kane et al defining treatment resistance in schizophrenia has relaxed with time. Most agree that failure to respond to adequate trials of two agents is necessary for the definition of treatment resistance.