Sulpride and sulpiride constitute another class of atypical agents. They have equivalent potency for D2 and D3 receptors, but they are also 5-HT7 antagonists. They dissociate EPS and anti-psychotic efficacy. However, they also produce marked increases in serum prolactin levels and are not as free of the risk of tardive dyskinesia as are drugs such as clozapine and quetiapine. They are not approved in the USA.
Cariprazine represents another second-generation agent. In addition to D2/5-HT2 antagonism, cariprazine is also a D3 partial agonist with selectivity for the D3 receptor. Cariprazine’s selectivity for the D3 receptor may be associated with greater effects on the negative symptoms of schizophrenia. This drug was approved in 2015 in the USA.
F. Glutamatergic Antipsychotics
No glutamate-specific agents are currently approved for the treatment of schizophrenia. However, several agents are in late clinical testing. Among these is bitopertin, a glycine transporter 1 (GlyT1) inhibitor. As noted earlier, glycine is a required co-agonist with glutamate at NMDA receptors. Initial phase 2 studies indicated that bitopertin used adjunctively with standard antipsychotics significantly improved negative symptoms of schizophrenia, but subsequent trials have been disappointing. Sarcoserine (N-methylglycine), another GlyT1 inhibitor, in combination with a standard antipsychotic has also shown benefit in improving both negative and positive symptoms of schizophrenia in acutely ill as well as in more chronic patients with schizophrenia.
Another class of investigational antipsychotic agents includes the metabotropic glutamate receptor agonists. Eight metabotropic glutamate receptors are divided into three groups: group I (mGluR1,5), group II (mGluR2,3), and group III (mGluR4,6,7,8). mGluR2,3 inhibits glutamate release presynaptically. Several mGluR2,3 agents are being investigated in the treatment of schizophrenia. One agent, pomaglumetad methionil, showed antipsychotic efficacy in early phase 2 trials, but subsequent trials failed to show benefit in either positive or negative symptoms of schizophrenia. Other metabotropic glutamate receptor agonists are being explored for the treatment of negative and cognitive symptoms of schizophrenia.
A. Absorption and Distribution
Most antipsychotic drugs are readily but incompletely absorbed. Furthermore, many undergo significant first-pass metabolism. Thus, oral doses of chlorpromazine and thioridazine have systemic availability of 25–35%, whereas haloperidol, which has less first-pass metabolism, has an average systemic availability of about 65%.
Most antipsychotic drugs are highly lipid soluble and protein bound (92–99%). They tend to have large volumes of distribution (usually more than 7 L/kg). They generally have a much longer clinical duration of action than would be estimated from their plasma half-lives. This is paralleled by prolonged occupancy of D2 dopamine receptors in the brain by the typical antipsychotic drugs.
Metabolites of chlorpromazine may be excreted in the urine weeks after the last dose of chronically administered drug. Long-acting injectable formulations may cause some blockade of D2 receptors 3–6 months after the last injection. Time to recurrence of psychotic symptoms is highly variable after discontinuation of antipsychotic drugs. The average time for relapse in stable patients with schizophrenia who discontinue their medication is 6 months. Clozapine is an exception in that relapse after discontinuation is usually rapid and severe. Thus, clozapine should never be discontinued abruptly unless clinically needed because of adverse effects such as myocarditis or agranulocytosis, which are true medical emergencies.
B. Metabolism