Pharmacological Properties History

Antipsychotics, as we use the term now, were introduced into clinical psychiatry in the 1950s. They were originally called neuroleptics, a term still broadly used in medical jargon which is derived from Greek and loosely translated as "grasping the nerve.'' This reflects the fact that originally the sedative effects of these drugs were in the foreground of clinical interest. This was also the origin of the American term "major tranquilizers."

Over the last two decades antipsychotics has become the preferred term for this class of drugs based on their main indications and clinical effect. While it was originally felt that antipsychotic efficacy was inextricably linked to

► extrapyramidal motor side-effects (EPS), the introduction of ► clozapine in the early 1970s demonstrated that this was not the case, as this drug proved to be an excellent antipsychotic with only a minimal risk to induce EPS. This also triggered a new classification of antipsychotics, which had so far been differentiated either by their chemical structure (e.g., ► phenothiazines, ► thioxanthenes, and ► butyrophenones) or their affinity to the dopamine D2 receptor (high and low potency neuroleptics). The fact that clozapine was found to be an effective antipsychotic without inducing motor side-effects was considered an "anomaly," and the term "atypical" was coined to describe clozapine and to differentiate it from the older "typical" drugs with their considerable potential for such adverse events. Consequently, antipsychotics which were developed following clozapine's introduction and which shared at least some of its characteristics were also subsumed under the category "► atypical antipsychotics." It soon became clear that "atypical antipsychotics" represent a rather inhomogeneous group, both from preclinical and clinical pharmacological perspectives. As the receptor pharmacology of these drugs is complex and provides no solid basis for differentiation, the field agreed upon classifying these drugs based upon a less contentious base, namely a more historical dimension. Thereby, all drugs developed until the advent of clozapine were called ► firstgeneration antipsychotics (or sometimes "classical" or "traditional") while the drugs that were introduced after clozapine and shared its low risk for EPS are now called

► second-generation antipsychotics. We are now on the threshold of a ► third-generation of antipsychotics, initiated with the registration of ► aripiprazole, the first licensed antipsychotic which is not a D2 antagonist.

Mechanisms of Action

It took about 10 years after the clinical efficacy of these drugs had been established until it was realized that anti-psychotics block ► dopamine receptors. This finding can be seen as the cornerstone of the dopamine hypothesis of schizophrenia. More than adecade later, Seeman et al.

(1976) published their classic paper on the correlation between D2 dopamine receptor affinity and clinically effective doses of antipsychotics, demonstrating that drugs with high receptor affinity required lower doses than drugs with lower affinities. All currently licensed antipsychotics with the exception of aripiprazole, a partial D2 agonist, block postsynaptic dopamine D2 receptors. The fact that most of these drugs also influence other receptor systems has given rise to a number of alternative attempts to achieve antipsychotic effects. The most prominent targets were various subtypes of the serotonin receptor (e.g., 5HT2A, 5HT1a) and lately the glutamatergic system, including both ionotropic and ► metabotropic receptors (Miyamoto et al. 2003).

Countless clinical and preclinical experiments link the effects of antipsychotics to the dopaminergic system. In very general terms, the acute administration of anti-psychotics leads to an increased firing rate and neuro-transmitter turnover in dopaminergic neurons while these effects are reversed after chronic administration (Grace 1992). In this respect older drugs, such as ► haloperidol, are different from newer ones such as clozapine insofar as haloperidol demonstrates these characteristics both in neurons originating in the substantia nigra (A9 dopaminergic neurons) as well as in those which project from the ventral tegmentum (A10 neurons) while clozapine only blocks A10 neurons. This has been replicated many times using different electrophysiological, neurochemical, and imaging techniques and is considered the reason why clozapine exerts antipsychotic effects without affecting the motor system (Miyamoto et al. 2003).

Clinically, the introduction of single photon emission tomography (► SPECT) and positron emission tomography (► PET) have provided the most relevant neurobio-logical leads into the effects of antipsychotics in humans. All available antipsychotics bind to striatal (and possibly extrastriatal) dopamine receptors in varying degrees. A dose-response relationship between human D2 receptor affinity and clinical profile is very likely, albeit it is challenged by the findings that the highly effective anti-psychotic clozapine and also ► quetiapine only loosely bind to this receptor (Stone et al. 2009).

In summary, all evidence taken together clearly points to a disruption of dopaminergic function in schizophrenia patients and strongly suggests that a restoration of balance in this system contributes to the therapeutic efficacy of antipsychotics.

As outlined earlier, other receptor systems have also been investigated in this context. As clozapine has high affinity to a number of other neurotransmitter receptors (including ► serotonin, histamine, and ► noradrenaline), these systems have been explored regarding their potential contribution to the drug's benefit-risk profile. The hypothesis most vigorously explored was the one that linked its serotonin (5HT2) antagonist properties to the clinical profile. In conjunction with previous preclinical research which had found that serotonin antagonists can counteract extrapyramidal motor side-effects of neuroleptics, Meltzer et al. (1989) formulated the hypothesis that 5HT2 antagonism which is proportionally larger than D2 antagonism is responsible for the advantages that clozapine and all other drugs sharing this profile have over the older drugs in terms of lower EPS risk. In addition, they and other authors feel that these pharmacological characteristics also contribute to enhanced clinical efficacy, especially with regard to negative symptoms and cognitive impairment. Although an intriguing and well thought through hypothesis, it is somewhat challenged by the pure dopamine antagonist ► amisul-pride which has no direct effects on the serotonergic systems, yet shares a lot of the clinical effects with 5HT2/D2 antagonists (McKeage and Plosker 2004).

The glutamate system is intricately linked with dopa-minergic neurotransmission throughout the central nervous system (CNS), a topic reviewed by Carlsson et al. (2001). It functions as a modulator of dopaminergic neurotransmission. This has led to a number of clinical experiments aiming at investigating drugs that do not directly act via the dopaminergic systems. Both the glycine sites of ► NMDA receptors and ► metabotropic glutamatergic receptors have been the targets of such investigations. Clinical studies are encouraging but have not yet led to licensed medications (Miyamoto et al. 2005).

Other neurotransmitter systems have mostly been considered in the context of drug safety. Many antipsy-chotics which block noradrenergic a1 receptors have been found to affect blood pressure. Antihistamine effects have been related to sedation and weight gain, just to provide a few examples.

Animal Models

There is no reliable and valid animal model for schizophrenia. All available models are either derived from the dopamine hypothesis of schizophrenia or from the actions that effective antipsychotics induce in laboratory animals. Many of them are related to non-therapeutic effects of antipsychotics such as those which affect the motor system. At the most, we may optimistically assume that these models are in some approximation to the clinical syndrome of the disorder. Nevertheless, animal models, imperfect as they may be, are still a cornerstone of antipsychotic drug development (Lipska and Weinberger 2003). Conditioned ► active avoidance is a classic among these models. All antipsychotics block conditioned avoidance and this test is therefore one of the early screening experiments in the development of potential antipsychotics.

Another set of experiments involve the various motor effects of this class of drugs. Spontaneous locomotor activity as well as pharmacologically enhanced psychomo-tor activity is usually decreased after the administration of antipsychotic drugs. First- and second-generation anti-psychotics are nicely differentiated by the dose needed to induce catalepsy, which is a good indicator for clinical EPS risk.

More recent models which can also be performed in humans include various variants of sensory motor gating studies. One example for these is ► prepulse inhibition (PPI), which is based on the finding that a weak prepulse reduces the startle reflex to a given, usually acoustic, stimulus. It is seen as part of the information processing capabilities of the CNS. PPI can be disrupted by both dopamine agonists and NMDA antagonists, thereby providing a model within the dopamine/glutamate hypothesis of schizophrenia. As antipsychotics restore PPI in animals in which it has been disrupted, such sensory motor gating models are also seen as indicative of potential antipsychotic effects.

► Pharmacokinetics

Antipsychotics are generally well absorbed and most of them are metabolized by hepatic ► cytochrome P450 isoenzymes. They are generally highly lipophilic and therefore cross the ► blood-brain barrier well and accumulate in fatty tissues. The benzamides ► sulpiride and ► ami-sulpride are an exception to these rules.

The elimination half-lives of antipsychotics are distributed over a wide range between a few hours (► que-tiapine) and days (aripiprazole). Steady-state levels differ accordingly, but as a rule of thumb once-daily dosing is possible. It is important to note that elimination from the brain and the drugs' target organs has been shown to be much slower than from plasma (Gruender 2007).

Given that all drugs with the exception of the benza-mides are metabolized via cytochrome isoenzymes in the liver, the potential for interactions with other drugs which compete for these enzymes needs to be considered. Phar-macodynamic interactions are to be expected when anti-psychotics are coadministered with drugs that target the same receptor systems, either centrally or peripherally. These include drugs with antihistamine and antiadrener-gic effects which can lead to a potentiation of sedation, weight gain, or hypotensive adverse events.


Next to antipsychotic effects, i.e., reducing ► delusions and ► hallucinations, most antipsychotics also have sedative properties. Furthermore, they have been shown to reduce negative symptoms, enhance cognitive functions, ameliorate affective symptoms (both manic and depressive) in patients suffering from schizophrenia and, most likely as a secondary effect, improve the quality of life and psychosocial reintegration (Miyamoto et al. 2003). Although most research with antipsychotics has been performed in schizophrenia patients, the therapeutic actions of these drugs extend beyond this diagnosis. Indications include mania, psychotic depression, ► schizoaffective disorder, ► bipolar depression, psychotic symptoms in the context of organic disorders from delirium to ► dementia, personality disorders, and treatment-resistant obsessive compulsive disorder, just to list the better researched disorders. As most of these are be covered in other entries, only general treatment principles in schizophrenia patients are briefly reviewed.

Recent evidence indicates that the onset of antipsy-chotic action in schizophrenia can be seen within days of commencing treatment (Agid et al. 2006), although it may take up to 6 months to achieve full remission of symptoms. Close to two thirds of first-episode schizophrenia patients reach symptom remission within this time if the duration of previously untreated psychosis is not too long. Response patterns become less favorable with increasing chronicity of the disorder. Next to acute symptom control and stabilization, antipsychotics also have powerful relapse-preventing properties (Kane 2007). Regularly taking medication over long periods of time protects about 80% of patients from a psychotic relapse. Having said that, compliance is one of the major challenges of the long-term management of schizophrenia (Fleischhacker et al. 2003). To aid uninterrupted dosing, depot antipsychotics that are injected at regular, long intervals have been developed. So far ► risperidone and ► olanza-pine are the only second-generation antipsychotics available for this method of administration (Fleischhacker 2009).

Clozapine plays a special role in the management of schizophrenia. On the one hand, it is the drug of choice in patients with a treatment-resistant course of the disorder; on the other hand, it has a 1% risk to induce agranulocy-tosis which makes it a third line drug despite its excellent efficacy (Tandon et al. 2008).


For first-generation antipsychotics, sedation as well as acute and tardive extrapyramidal motor side effects represented the biggest safety obstacles that also translated into tolerability and compliance problems. Next to that, these drugs, depending on their receptor profiles, induced a number of other adverse events including anticholin-ergic side effects, orthostatic hypotension, weight gain, hormonal aberrations including sexual disturbances, der-matologic problems including acne-like manifestations and photosensitivity, disturbances of gastrointestinal mo-tility, hematological side effects, cardiac arrhythmias, seizures, and the ► neuroleptic malignant syndrome, just to name the clinically most relevant. Apart from potentially life-threatening adverse events such as clozapine-induced agranulocytosis, tachyarrhythmia, and the neuroleptic malignant syndrome, many of these side effects constitute problems affecting subjective tolerability rather than objective health risks. Prevalence rates differ considerably between drugs, and the incidence of these side effects is difficult to predict on an individual level. Therefore, patients treated with antipsychotics have to be well informed and monitored regularly.

Second-generation antipsychotics as a group have a considerably lesser risk to induce EPS than the older drugs. This applies to both frequency and severity of acute and chronic motor side effects. Some of these drugs, most notably clozapine and olanzapine, have a substantial propensity to induce weight gain and metabolic disturbances such as hyperlipidemia and reduced insulin sensitivity. Apart from these concerns the newer drugs appear to be tolerated appreciably better than traditional neuroleptics. Clearly, despite this, the same recommendations regarding patient information and monitoring must be followed (Miyamoto et al. 2003).


In summary, antipsychotics represent a crucial component of the pharmacotherapeutic options in psychiatry. A large array of effective drugs is available. Antipsychotics are employed over a broad range of indications with a very favorable benefit-risk profile. It is hoped that their main therapeutic limitations, namely efficacy beyond psychotic symptoms, will be overcome with the exploration of pharmacologic mechanisms which extend beyond the dopamine system.

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