Antipsychotic drugs therapeutic actions

Grace AA, Bunney BS, Moore H, Todd CL (1997) Dopamine-cell depolarization block as a model for the therapeutic actions of antipsychotic drugs. TINS 20 31-37... 

Strange, P. G. Antipsychotic drugs importance of dopamine receptors for mechanisms of therapeutic actions and side effects. Pharmacol. Rev. 53 119-133, 2001. 

The blockade of dopamine receptors by antipsychotic drugs is an immediate effect that can be detected even after a single dose, whereas the therapeutic action of these drugs becomes apparent only after several days or weeks of treatment. 

The earliest effective treatments for schizophrenia and other psychotic illnesses arose from serendipitous clinical observations rather than from scientific knowledge of the neurobiological basis of psychosis or the mechanism of action of effective antipsychotic agents. Thus, the fist antipsychotic drugs were discovered by accident in the 1950s when a putative antihistamine (chlorpromazine) was serendipitously observed to have antipsychotic effects when tested in schizophrenic patients. Chlorpromazine indeed has antihistaminic activity, but its therapeutic actions in schizophrenia are not mediated by this property. Once chlorpromazine was observed to be an effective antipsychotic agent, it was tested experimentally to uncover its mechanism of antipsychotic action. 

It should now be obvious that the use of conventional antipsychotic drugs presents a powerful dilemma. That is, there is no doubt that conventional antipsychotic medications have dramatic therapeutic actions on positive symptoms of psychosis by blocking hyperactive dopamine neurons in the mesolimbic dopamine pathway. However, there are four dopamine pathways in the brain, and it appears that blocking dopamine receptors in only one of them is useful, whereas blocking dopamine receptors in the remaining three pathways may be harmful. 

Newton SS, Duman RS. 2007. Neurogenic actions of atypical antipsychotic drugs and therapeutic implications. CNS Drugs 21 715-725. 

The first intracellular effect mediated by dopamine receptors that has been reported was the stimulation of the production of cyclic AMP (cAMP) in target cells. This effect was originally described in the superior cervical ganglia and the cow retina (Kebabian and Greengard, 1971 Brown and Makman, 1972) and soon afterward, in the CNS, in rat striatum (Kebabian et al., 1972). Antipsychotic drugs were found to block this response (Clement-Cormier et al., 1974 Miller et al., 1974) and this was the first direct evidence supporting the hypothesis proposed by A. Carlsson in the 1960s that the therapeutic actions of neuroleptics result from their ability to block dopamine receptors. 

There is ample evidence from preclinical and clinical research that the glutamatergic system is involved in the pathophysiology of mood disorders and that many of the somatic treatments used in the treatment of mood disorders, including current conventional antidepressants, mood stabilizers, atypical antipsychotic drugs, and electroconvulsive therapy, have direct and indirect inhibitory effects on the glutamatergic system.The monoamine-based therapies (i.e. the currently available antidepressants) ultimately inhibit the N-methyl-D-aspartate (NMDA) receptor for glutamate (although it is not classically conceived as their main therapeutic action). 

Strange PG Antipsychotic Drugs Importance of Dopamine Receptors for Mechanisms of Therapeutic Actions and Side Effects, Pharmacol. Rev, 53 119, 2001. 

In this age of sophisticated drug design and biotechnolcgy, the simple lithium ion is still the most effective treatment of this destructive psy-cholcgical disorder. Remarkably, in spite of intensive research, scientists still do not fully understand the biochemical action of lithium that leads to its therapeutic effects. Because of its similarity to Na, Li" is incorporated into blood plasma, where it can affect the behavior of nerve and muscle cells. Because Li has a smaller radius than Na (Figure 7.7), the way Li interacts with molecules in human cells is different from the way Na interacts with the molecules. Other studies indicate that Li alters the function of certain neurotransmitters, which might lead to its effectiveness as an antipsychotic drug. 

Unfortunately, few of the studies that have attempted to relate the blood concentrations of neuroleptics to therapeutic response have fulfilled all these criteria. There is a suggestion that a "thera peutic window" exists for some phenothiazine neuroleptics. A therapeutic window is a range of concentrations of a drug measured in the blood that are associated with a good therapeutic response. Plasma concentrations outside this range are either too low to ensure a therapeutic response or so high that they induce toxic side effects. Despite the numerous studies of the relationship between the plasma concentration and the therapeutic response for a number of "standard" neuroleptics, it would appear that such correlations rarely account for more than 25% of the variance in clinical response to treatment. The existence of a therapeutic window for neuroleptics would therefore appear to be unproven. However, there could be ranges of plasma concentrations associated with optimal antipsychotic action, but these... 

The antischizophrenic actions of these drugs may not consist simply of postsynaptic blockade of hyperactive dopamine systems. Such a blockade occurs within hours, while most symptoms improve over weeks. This discrepancy in the latency to therapeutic effect has been hypothesized to be linked to drug-induced changes in dopaminergic activity after initiation of therapy, dopamine turnover increases, but after continued antipsychotic treatment, tolerance develops and dopamine metabolism returns to normal. This downward adjustment of dopaminergic activity is consistent with the decreased plasma concentrations of the dopamine metabolite homovanillic acid, an observation that correlates temporally with the clinical response to drug treatment. 

Dean B, Scarr E. Antipsychotic drags evolving mechanisms of action with improved therapeutic benefits. Curr Drug Targets CNS Neurol Disord. 2004 3 217-225. 

Other classes of drugs not included in Figure 22-3 that may exert sedative effects include most antipsychotic and many antidepressant drugs and certain antihistaminic agents (eg, hydroxyzine, promethazine). As discussed in other chapters, these agents differ from conventional sedative-hypnotics in both their effects and their major therapeutic uses. Since they commonly exert marked effects on the peripheral autonomic nervous system, they are sometimes referred to as "sedative-autonomic" drugs. Certain antihistaminics with sedative effects are available in over-the-counter sleep aids. Their autonomic properties and their long durations of action can result in adverse effects. 

Unlike antipsychotic or antidepressant drugs, which exert several actions on the central or autonomic nervous system, lithium ion at therapeutic concentrations is devoid of autonomic blocking effects and of activating or sedating effects, though it can produce nausea and tremor. 

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