Glutamatergic neurotransmission modulation and the mechanisms of antipsychotic atypicality

The neurotransmission mediated by the excitatory amino acids (EAA) glutamate (GLU) and aspartate is of interest to the pharmacotherapy of psychosis due to its role in neurodevelopment and neurotoxicity, its complex interactions with dopaminergic and other neurotransmitter systems and its pivotal importance in recent models of schizophrenia. Accumulating evidence indicates that modulation of glutamatergic neurotransmission may play an important role in the mechanisms of action of atypical antipsychotic drugs. The principles of the phencyclidine (PCP) model of schizophrenia suggest that conventional neuroleptics cannot counteract all aspects of schizophrenia symptomatology, while a more favorable outcome, including anti-negative and cognitive symptoms effects, would be expected with the use of treatment modalities targeting glutamatergic neurotransmission. Clozapine and other presently used atypical antipsychotics differ from conventional neuroleptics in the way they affect various aspects of glutamatergic receptors function. In this context, a specific hypothesis suggesting an agonistic role of clozapine at the N-methyl-D-aspartate (NMDA) subtype of GLU receptors has been postulated. Furthermore, the results of the first generation of clinical trials with glycine (GLY) site agonists of the NMDA receptor in schizophrenia suggest that this type of compounds (1) have efficacy and side effects profiles different than those of conventional neuroleptics and (2) differ in their synergic effects when used in addition to conventional neuroleptics versus clozapine and possibly additional atypical antipsychotics. These findings (1) bring further support to the hypothesis that glutamatergic effects may play an important role in the mechanism of action of atypical antipsychotics, (2) help explain the unique clinical profile of clozapine, and (3) suggest that GLY site agonists of the NMDA receptor may represent a new class of atypical antipsychotic medication. Future research in this area is bound to bring about a better understanding of the role of glutamatergic neurotransmission manipulation in the pharmacotherapy of psychosis and the development of novel pharmacological strategies targeting GLU brain systems.     

Muscarinic mechanisms of antipsychotic atypicality

The interactions of the atypical antipsychotic drugs (APD) clozapine, olanzapine, risperidone, quetiapine and ziprasidone with muscarinic receptors were reviewed. Only clozapine and olanzapine have marked affinity for muscarinic receptors in radioligand binding studies; however, the affinity of these compounds is considerably lower than classical muscarinic antagonists. Although functional assays in cell lines transfected with muscarinic receptors suggest that olanzapine and clozapine have weak partial agonist activity at muscarinic receptors, particularly M4 receptors, studies in vitro and in vivo indicate that the compounds function as antagonists. In animal studies and in humans, clozapine has pronounced antimuscarinic effects whereas olanzapine has weak antimuscarinic effects. However, olanzapine significantly occupies central muscarinic receptors in humans. Overall, the role of muscarinic receptors in the antipsychotic effects of clozapine and olanzapine is controversial and complex.     

Animal behavior models of the mechanisms underlying antipsychotic atypicality

This review describes the animal behavior models that provide insight into the mechanisms underlying the critical differences between the actions of typical vs. atypical antipsychotic drugs. Although many of these models are capable of differentiating between antipsychotic and other psychotropic drugs, only a few seem to be able to differentiate between typical and atypical antipsychotics, such as the paw test and the phencyclidine (PCP)-induced disruption of prepulse inhibition (PPI) of startle in rats. Moreover, there is an urgent need for animal models focusing more on the negative and the cognitive symptoms. Hence, improved animal models are crucial for developing better treatments for schizophrenia.     

Amisulpride: limbic specificity and the mechanism of antipsychotic atypicality

Amisulpride clearly has the clinical profile of an atypical antipsychotic, characterised in particular by its lower propensity to induce extrapyramidal side effects as well as its greater efficacy in treating negative symptoms compared with classical neuroleptics. In addition to the clinical advantages over classical neuroleptics, it has also been demonstrated that the clinical profile of amisulpride is comparable to that of other modern atypical neuroleptics. Animal data also allow the conclusion to be drawn that amisulpride has an atypical profile. For example, amisulpride does not provoke catalepsy which is characteristic of postsynaptic D2 blockade in the rat. The induction of catalepsy in animal models is usually seen as an indicator of the propensity to induce extrapyramidal side effects in patients. In relation to the widely accepted hypothesis that the inclusion of 5-HT2A antagonism in addition to D2 antagonism is of great relevance for the atypicality of an antipsychotic, and given the fact that amisulpride lacks 5-HT2A antagonism, the pharmacological explanation of the clinically well-proven atypicality of amisulpride is of great interest. Based on basic research and in vivo imaging studies, two mechanisms in particular seem to explain the atypicality of amisulpride: preferential action on limbic D2/D3 receptors and preferential blockade of presynaptic D2/D3 receptors. In addition, the fast dissociation hypothesis can contribute to the explanation of the atypical clinical profile of amisulpride. The relevance of the D3 blockade in the context of atypicality is not yet completely clear.     

The dopamine D4 receptors and mechanisms of antipsychotic atypicality

The dopamine D4 receptor (D4) is a target for most common neuroleptic medications. After its initial discovery, it was found to possess the highest affinity of all dopamine receptor subtypes for the archetypical, atypical, antipsychotic clozapine. Nevertheless, initial clinical trials have not provided evidence that this receptor is a primary target for antipsychotic drugs. Considering the accumulated in vivo evidence that at least a subgroup of psychotic patients have altered dopamine signaling, all dopamine receptor subtypes likely contribute to the phenotypic expression of schizophrenia. New insights into the function of this receptor and its role in the modulation of excitatory signaling support the view that this dopamine receptor may affect attention and cognition. In this review, the authors outline some recent developments that provide insight into D4 receptor physiology, function and its possible relationship to schizophrenia treatment.     

Understanding antipsychotic "atypicality": a clinical and pharmacological moving target

The introduction of a number of new antipsychotics in the last decade has generated considerable excitement regarding the treatment of schizophrenia and related psychotic conditions. Clinically, it has produced changing expectations regarding treatment outcome, while academically it has encouraged a re-evaluation and expansion of theories of the pathophysiology of schizophrenia and antipsychotic activity. In this review, the development of antipsychotics is traced, beginning with chlorpromazine's introduction in the early 1950s, and followed to the present. Despite 50 years of use and a plethora of antipsychotics available worldwide, our conceptualization of their major mode of action remains essentially unchanged. It was shortly after their development that attention turned to the importance of dopamine, and in particular the dopamine D2 receptor. Current thinking has elaborated on this model, with serotonin and glutamate receiving the greatest attention most recently, but D2 antagonism remains the sine qua non of antipsychotic activity. Although the notion of "atypical" remains somewhat of a moving target, we do have at our disposal a new generation of antipsychotics that reflect a different clinical profile from their conventional counterparts. The precise degree of these differences and the underlying mechanisms remain unclear, however. The direction new antipsychotic development takes will undoubtedly hinge on answers to these questions.     

Delayed-onset hypothesis of antipsychotic action: a hypothesis tested and rejected

CONTEXT: To understand the mechanism of action of antipsychotic drugs, it is critical to recognize the time course over which these medications take effect. Current models of antipsychotic action presume a "delayed onset" of action. OBJECTIVE: To test the delayed-onset hypothesis of antipsychotic action via a meta-analytic study. DATA SOURCES AND STUDY SELECTION: Double-masked studies that reported results from active or placebo-controlled trials of antipsychotic response during the first 4 weeks of treatment were selected. These studies were identified by searching MEDLINE, 1996 to 2001; the Cumulative Index to Nursing and Allied Health, 1982 to 2001; EMBASE, 1980 to 2001; the ACP Journal Club; the Cochrane Database of Systematic Reviews; and the Database of Abstracts of Reviews of Effectiveness. Leads from these sources were followed up by manual searches. DATA SYNTHESIS: Forty-two published studies, including 7450 patients and 119 independent response vs time curves, were identified. Reductions in total scores on the Brief Psychiatric Rating Scale and the Positive and Negative Syndrome Scale were 13.8% during week 1, 8.1% during week 2, 4.2% during week 3, and 4.7% during week 4. This pattern of "early-onset" improvement was present even after the estimated effect of placebo treatment was removed and when results were restricted to the psychotic subscales of the scales. CONCLUSIONS: This analysis rejects the commonly held hypothesis that antipsychotic response is delayed. Rather, these findings suggest that the antipsychotic response starts in the first week of treatment and accumulates over time. Furthermore, greater improvement occurs in the first 2 treatment weeks than in the subsequent 2 treatment weeks. Proposed mechanisms of action of antipsychotic drugs need to account for this early-onset antipsychotic effect.     

History of the dopamine hypothesis of antipsychotic action

The dopamine hypothesis of how antipsychotic drugs exert their beneficial effect in psychotic illness has an interesting history that dates back to 1950. This hypothesis is not to be confused with the dopamine hypothesis of schizophrenia; the aim of the latter is to explain the etiology of schizophrenia. The present review does not deal with schizophrenia but, rather, with the historical development of our current understanding of the dopamine-associated actions of the drugs that reduce the symptoms of psychosis. This historical review begins with the serendipitous discovery of chlorpromazine, a drug synthesized around a chemical core that initially served to produce man-made dyes. This molecular core subsequently contributed to the chemistry of antihistamines. It was with the aim of producing a superior antihistamine that chlorpromazine was synthesized; instead, it revolutionized the treatment of psychosis. The first hypothesis of how this drug worked was that it induced hypothermia, a cooling of the body that led to a tranquilization of the mind. The new, at the time, discoveries of the presence of chemical transmitters in the brain soon steered investigations away from a temperature-related hypothesis toward questioning how this drug, and other drugs with similar properties and effects, modulated endogenous neurotransmission. As a result, over the years, researchers from around the world have begun to progressively learn what antipsychotic drugs do in the brain.     

Early-onset hypothesis of antipsychotic drug action: a hypothesis tested, confirmed and extended.

BACKGROUND: A recent meta-analysis rejected the "delayed onset of antipsychotic action hypothesis" that had been described in textbooks for decades. Since meta-analyses are prone to a number of methodological problems, we attempted a replication by a) using a large database of individual patient data rather than meta-analysis, b) including another antipsychotic and c) extending the analysis from four weeks to one year. METHODS: We pooled the data of seven randomized trials involving amisulpride. The data included 1708 patients with schizophrenia and positive symptoms and we examined the incremental percentage Brief Psychiatric Rating Scale (BPRS) reduction over time. RESULTS: The "early onset of antipsychotic action hypothesis" was confirmed, as the reduction of overall and positive symptoms until week two was larger than the additional reduction until week four (p<.0001). Furthermore, in a subset with long-term data (n=748) approximately 68% of the mean BPRS change at one year was already achieved at four weeks in the observed cases. CONCLUSIONS: A substantial amount of the antipsychotic drug effect seems to occur during the first weeks of treatment. Subsequent analyses are needed to establish how long an antipsychotic should be tried before it is considered ineffective and alternative strategies implemented.     

Ascorbic acid and atypical antipsychotic drugs: modulation of amineptine-induced behavior in mice

To provide a detailed characterization of individual kinds of behavior produced by ascorbic acid in combination with typical haloperidol) or atypical (clozapine, sulpiride and remoxipride) antipsychotic drugs, the ‘open-field’ test was selected. Amineptine, an indirect dopamine agonist, was used as an explicit model of dopaminergic activity. Results showed that amineptine (5–10–20 mg/kg i.p.), dose-dependently increased ambulation and rearing. Ascorbic acid (62.5–125–250 mg/kg i.p.) markedly inhibited the behavior of mice as well as the amineptine-induced hyperactivity. A combination of each typical or atypical antipsychotic drug (except clozapine 2.5 mg/kg i.p.) with amineptine (20 mg/kg i.p.) induced a significant increase in ambulation and rearing over that seen with the antipsychotic drugs alone. The combination of antipsychotic drugs with ascorbic acid 250 mg/kg i.p. led to a decrease in open-field parameters when compared with controls. In conclusion, these data provide further in vivo support for the effect of ascorbic acid on dopaminergic system and demonstrate that the antidopaminergic effects of both typical and atypical antipsychotic drugs may be enhanced with concurrent administration of ascorbic acid.     

The role of melatonin in the antipsychotic and motor-side effects of neuroleptics: a hypothesis.

Three phenomena concerning the antipsychotic action of classic neuroleptic drugs have not been adequately explained by the dopamine hypothesis: (1) administration of neuroleptic drugs is commonly associated with an initial period of 3-6 weeks prior to demonstration of antipsychotic effects; (2) similarly, neuroleptic-induced Parkinsonism commonly emerges only after several weeks of neuroleptic therapy; (3) moreover, Parkinsonism may disappear despite continuous neuroleptic treatment. An understanding of these phenomena might shed new light into the nature of the antipsychotic actions of these agents, and hence the pathophysiology of schizophrenia. We propose that the increase in melatonin secretion, which occurs with the initiation of neuroleptic therapy, may be responsible for the delay in the antipsychotic effects of neuroleptics and may also account for the lag in the development of drug-induced Parkinsonism as well as its disappearance. The implications of this hypothesis for the treatment of schizophrenia and the prophylaxis of drug-induced Parkinsonism are discussed.     

Extrapyramidal side effects, tardive dyskinesia, and the concept of atypicality

The most frequent problems associated with the older generation of antipsychotic agents are extrapyramidal side effects (EPS) and tardive dyskinesia. Neuroleptic-induced EPS are thought to be caused by blockade of nigrostriatal dopamine tracts resulting in a relative increase in cholinergic activity; tardive dyskinesia is less well understood but is thought to be a supersensitivity response to chronic dopamine blockade. The leading hypothesis for the mechanism of action of the newer generation of atypical antipsychotics is the presence of a high serotonin-to-dopamine receptor blockade ratio in the brain. When serotonergic activity is blocked-as is the case with atypical antipsychotics-dopamine release increases and balances out the dopamine blockade effect at postsynaptic receptor sites, which results in few or no EPS. Prospective data indicate that the risk of tardive dyskinesia in patients taking atypical antipsychotics is less than that for those taking typical antipsychotics. This article reviews the mechanisms of neuroleptic-induced EPS and tardive dyskinesia and discusses the relationship between these movement disorders and atypical antipsychotic agents.