Possible Dose-Side Effect Relationship of Antipsychotic Drugs: Relevance to Cognitive Function in Schizophrenia

Tomiki Sumiyoshi

Disclosures

Expert Rev Clin Pharmacol. 2008;1(6):791-802. 

In This Article

Abstract and Introduction

Abstract

Management of adverse events is a major concern of clinicians who use antipsychotic drugs. The incidence of motor side effects is dose dependent. Atypical antipsychotic drugs are less likely to induce neurologic side effects compared with typical (conventional) antipsychotics, such as haloperidol. Some recent, large-scale studies have shown that the incidence of metabolic side effects often associated with atypical agents does not differ among typical and atypical antipsychotics. Cognitive function, such as verbal learning memory, working memory, executive function, verbal fluency and attention/information processing, is the most influential determinant of outcome in patients with schizophrenia. Atypical antipsychotic drugs have been shown to be more efficacious in treating cognitive disturbances of schizophrenia compared with typical antipsychotic drugs. Serotonin (5-hydroxytryptamine [5-HT]) receptor subtypes, such as the 5-HT1A receptor, are considered to mediate the ability of antipsychotic drugs to enhance cognition. On the other hand, treatment with some atypical agents, such as risperidone, may deteriorate working memory in some people with early-stage schizophrenia. The paradoxical side effects of these antipsychotic drugs in terms of cognition may be attributable to dose, duration of treatment and type of cognitive domain. Further research will add to the worldwide endeavor to develop more effective psychotropic drugs accompanied with minimal side effects, for the improvement of cognition, adherence and long-term outcome in patients with schizophrenia or other major psychiatric illnesses.

Introduction

Since the discovery of chlorpromazine in the early 1950s, antipsychotic drugs have provided the most reliable and efficacious tools in the treatment of major psychiatric disorders, such as schizophrenia, schizoaffective disorders, mood disorders, substance abuse and dementias.[1–3]

The dopamine (DA) hypothesis of schizophrenia was postulated based on evidence from laboratory and clinical data indicating that DA supersensitivity in some of the subcortical brain regions (e.g., the striatum and nucleus accumbens) constitutes a neurochemical basis for positive psychotic symptoms (e.g., delusions and hallucinations).[4–6] Postmortem[7,8] and PET[9] studies have elicited upregulation of DA-D2 family receptor subtypes in the brain of subjects with schizophrenia, providing clinical evidence supporting the DA hypothesis. In animals, dysregulation of DA-related behaviors, including enhanced locomotor activity and stereotypy, as well as disrupted prepulse inhibition, have been thought to reflect psychosis-related symptoms.[5,6,10] Recently, the DA hypothesis has evolved to the concept that the high-affinity states of D2 receptors, or D2high, may play a major role in the development of psychosis.[5,6]

Consistent with this hypothesis, Seeman et al. provided the first demonstration of a linear relationship between clinical potencies of antipsychotic drugs and their affinity for D2 receptors in the brain[11,12] (see[13] for a review). This finding shaped the subsequent course of antipsychotic development. In fact, almost all of the antipsychotic drugs currently marketed for clinical use possess D2 antagonist actions, irrespective of chemical class, (e.g., phenothiazines, thioxanthenes, butyrophenones, diphenylbutylpiperidines, benzamides, dibenzodiazepines and benzisoxazoles).[2,3] Some of the novel agents (e.g., aripiprazole and bifeprunox) have been shown to act as partial D2 agonists, capable of opposing excessive activation of receptors in the target sites (e.g., limbic areas) while maintaining modest stimulation of other sites (e.g., striatum and frontal cortex).[14]

Another landmark hypothesis for the etiology of schizophrenia and action of antipsychotic drugs concerns the neurotransmitter serotonin (5-hydroxytryptamine [5-HT]). This concept is based on clinical observations that indole compounds (e.g., N,N-dimethyltryptamine, mescaline, psilocybin and lysergic acid diethylamide) are hallucinogenic, and is also supported by biological evidence that 5-HT1A , 5-HT2A , 5-HT2C , 5-HT3 , 5-HT6 and 5-HT7 genes and receptors play potential roles in psychosis, cognition and mood.[15–17] Specifically, postmortem studies have demonstrated decreased 5-HT2A receptor density and mRNA expression, as well as increased 5-HT1A receptor density, in the cerebral cortex of subjects with schizophrenia.[18–20]

Meltzer et al. reported the first data demonstrating that a relatively high affinity for the 5-HT2A receptor compared with the affinity for the D2 receptor provides a basis for the difference between 'atypical' and 'typical' antipsychotic agents,[21] which was confirmed by subsequent studies using experimental in vivo paradigms Figure 1.[22–26] Here, atypical antipsychotic drugs, or so-called second-generation antipsychotics, with clozapine as the prototype compound, are defined as an agent causing low incidence of extrapyramidal symptoms (EPS) at doses that demonstrate antipsychotic activity compared with first-generation antipsychotics, such as chlorpromazine, haloperidol and perphenazine.[16] This '5-HT2A/D2 hypothesis' has contributed to the development of most of the current generation of atypical antipsychotic agents, including risperidone, olanzapine, quetiapine, ziprasidone, melperone and perospirone, all of which have a higher affinity for 5-HT2A than for D2 receptors.[16,27–31]

In vivo serotonin-5-HT2A/dopamine-D2 receptor occupancy ratios of antipsychotic drugs. SGAs show relatively high serotonin-5-HT2A/dopamine-D2 receptor occupancy ratios in vivo, compared with the FGAs. [3H]-ketanserin and [3H]-YM-09151-2 were used to label 5-HT2A and D2 receptors, respectively. FGA: First-generation antipsychotic; SGA: Second-generation antipsychotic. Based on.[26]

Receptor binding profiles of several of the representative typical and atypical antipsychotic drugs, including those currently used for first-line treatment of schizophrenia, can be seen in Figure 2. With the exception of the typical antipsychotic haloperidol that mainly blocks D2 receptors, these compounds possess variable affinities for 5-HT1A, 5-HT2A, 5-HT6 and 5-HT7, as well as noradrenalin, histamine and muscarinic acetylcholine receptors.[31] These pharmacological properties are thought to mediate both unique efficacy (e.g., mood and cognition) and a series of side effects, as discussed later.

Pie charts of receptor affinity of antipsychotic drugs. Affinity ratios for various neurotransmitter receptors are shown; the sum of inverse of Ki values for these receptors is supposed to be 100% for each agent. Graphs for clozapine and lurasidone were based on independent experimental procedures from the rest of the compounds. 5-HT: 5-hydroxytryptamine (serotonin); D: Dopamine. Data are quoted and modified from.[31,107,108]

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....