Effects of antipsychotic drugs

More recently, two methodologically advanced studies have been published a comparison between four antipsychotic drugs in a trial of 14 weeks duration (Bilder et al., 2002, see Box 7.1) and a study of 2 years duration comparing an atypical with an older typical antipsychotic drug (Green et al., 2002). 

1 A Controlled Comparison between Four Antipsychotic Drugs 

The four drugs were administered by psychiatrists blinded to treatment group assignment of patients. The 14-week study consisted of an 8-week dose escalation and fixed dose and a 6-week variable-dose period. The mean dose levels (mg/day) of the four compounds after the first 8 weeks were 452 for clozapine. 20.2 for olanzapine. 8.3 for risperidone and 19.6 for haloperidol. Patients on haloperidol received prophylactic anticholinergic medication to prevent extrapyramidal symptoms, and a few other drugs were permitted to treat agitation and insomnia. 

The main findings with regard to drug effects on cognitive performance were as follows  

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Bunney, B.S. Aghajanian, G.K. and Roth, R.H. Dopaminergic neurons Effect of antipsychotic drugs and amphetamine on single cell activity. 

Lieberman JA, Stroup TS, McEvoy JP, et al. Clinical antipsychotic trials of intervention effectiveness (CATIE) investigators. Effectiveness of antipsychotic drugs in people with chronic schizophrenia. N Engl J Med 2005 353 1209-1223. 

Table 5.2 Pharmacogenetic studies on the effects of antipsychotic drugs... 

Changes in dopamine receptor density may be involved in the side effects of antipsychotic drugs 222... 

Shin, J.G., Soukhova, N. and Flockhart, D.A. (1999) Effect of antipsychotic drugs on human liver cytochrome P-450 (CYP) isoforms in vitro preferential inhibition of CYP2 D6. Drug Metabolism and Disposition, 27 (9), 1078-1084. 

The predominant mechanism by which currently available antipsychotic medications interfere with dopamine activity is by blockade of dopamine receptors on neurons innervated by dopamine nerve terminals. Of the five types of dopamine receptors, all antipsychotics share in common the fact that they block the dopamine type 2 receptor, also known as the D2 receptor, to a varying degree. Some of the atypical antipsychotics also block other dopamine receptors (see Table 13.5). The role of blockade of Dl, D3, D4, and other dopamine receptors in the therapentic effects of antipsychotic drugs remains unclear. Aripiprazole is an exception to this in that it is a partial agonist at the D2 receptor. 

Extrapyramidal symptoms may occur as a side-effect of antipsychotic drugs. 

TABLE 34.2 Significant Adverse Effects of Antipsychotic Drugs... 

Many side effects of antipsychotic drugs can be understood in terms of the drugs receptor-blocking properties. When antipsychotics reduce dopamine activity in the nigrostriatal pathway (via dopamine... 

Table 3.5 Effects of antipsychotic drugs in healthy subjects...

Most of the unwanted effects of antipsychotic drugs are extensions of their known pharmacologic actions (Tables 29-1 and 29-2), but a few effects are allergic in nature and some are idiosyncratic. 

Most patients are able to tolerate the antimuscarinic adverse effects of antipsychotic drugs. Those who are made too uncomfortable or who develop urinary retention or other severe symptoms can be switched to an agent without significant antimuscarinic action. Orthostatic hypotension or impaired ejaculation—common complications of therapy with chlorpromazine or mesoridazine—should be managed by switching to drugs with less marked adrenoceptor-blocking actions. 

FIGURE 8-1 Effects of antipsychotic drugs on dopamine synapses. Antipsychotics act as postsynaptic receptor antagonists to block the effects of overactive dopamine transmission. 

Tertiary-amine muscarinic receptor antagonists gain access to the central nervous system and are therefore the anticholinergic drugs used to treat parkinsonism and the extrapyramidal side effects of antipsychotic drugs. Specific agents used primarily for these conditions include benztropine mesylate (Cogentin) and trihexyphenidyl hydrochloride (Artane, others). 

Monti JM, Monti D (2004) Sleep in schizophrenia patients and the effects of antipsychotic drugs. Sleep Med Rev 8 133-148... 

Evidence for Neuroprotective Effects of Antipsychotic Drugs Implications for the Pathophysiology and Treatment of Schizophrenia... 

Lieberman, J., Stroup, T., McEvoy, J., Swartz, M., Rosenheck, R., Perkins, D., et al. (2005a). Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. New England Journal of Medicine, 353, 1209-1223. 

Effect of antipsychotic drugs on DISCI and dysbin-din expression in mouse frontal cortex and hippocampus. J Neural Transm 113 1337-1346. 

Lahti AC, Holcomb HH, Weiler MA, Medoff DR, Tamminga CA. 2003. Functional effects of antipsychotic drugs Comparing clozapine with haloperidol. Biol... 

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