In response to the extrapyramidal side effects that affected almost 40% of patients treated with first-generation antipsychotics (FGAs) in the 1960s, clozapine, the first atypical or second-generation antipsychotic was introduced to the European market in 1971.1 Clozapine offered a reduced rate of extrapyramidal side effects but at the cost of an increased risk of life-threatening agranulocytosis. Consequently, clozapine was quickly withdrawn from the market but later entered the U.S. market in 1990, accompanied by a Risk Evaluation and Mitigation Strategy for blood monitoring.

Shortly after the re-emergence of clozapine, numerous second generation antipsychotics (SGAs) hit the market, including risperidone (1994), olanzapine (1996), quetiapine (1997), ziprasidone (2001), aripiprazole (2002), and paliperidone (2006). These agents provided fewer extrapyramidal side effects compared to FGAs; however, they were associated with a greater likelihood of causing metabolic abnormalities. SGAs were also hypothesized to be more effective in treating the negative and cognitive symptoms of schizophrenia compared to FGAs. While the efficacy of FGAs and SGAs in relieving positive symptoms of schizophrenia has been well-established, the SGAs, with the exception of clozapine, have yet to prove clear and consistent superiority to FGAs in treating negative and cognitive symptoms of schizophrenia. Today, there are a total of ten SGAs available, three of which recently obtained FDA approval in 2009 and 2010, including iloperidone (Fanapt®), asenapine (Saphris®), and lurasidone (Latuda®). All three agents are indicated for the treatment of schizophrenia, and asenapine carries an additional indication for bipolar mania. Though these newer agents appear to be associated with fewer metabolic abnormalities than other SGAs, including, quetiapine and olanzapine, their enhanced efficacy in treating cognitive and negative symptoms has not yet been determined. While it's always exciting when new psychotropic agents come to market, we are tasked with determining how these agents fit into clinical practice, and comparing and contrasting these medications in terms of efficacy and tolerability, with alternative, less expensive medications already available. Since about 30% of patients with schizophrenia are considered treatment-refractory and more than 60% of patients fail to achieve remission, there is a strong need for more effective antipsychotic agents.2 Many antipsychotics in the pipeline are aimed at treating negative and cognitive symptoms of schizophrenia and focus on novel drug targets with mechanisms of action that differ from their antipsychotic predecessors.

According to an in press review article in Neuropharmacology, there are fourteen antipsychotics currently undergoing clinical trials, each aimed at ameliorating positive, negative, and cognitive symptoms of schizophrenia.3 Two of these antipsychotics are being evaluated in phase III trials and include cariprazine, a product of Gedeon Ritcher Ltd. and Forest Laboratories, and RG1678, a product of Roche.3 Cariprazine is a multiple dopamine (D2/D3) receptor antagonist as well as a 5HT1A partial agonist.3 In addition to D2 antagonism, many antipsychotics bind to D3 receptors, which is thought to further enhance antipsychotic efficacy.3 D3 receptors, which are preferentially located in the limbic system, have been found to be increased in patients with schizophrenia and are theorized to play a role in cognitive and emotional regulation.4 Thus, the implications of D3 antagonism and its role in the treatment of schizophrenia are currently being explored. Cognitive and negative symptoms of schizophrenia have also been attributed to a deficiency of dopamine in the prefrontal cortex.4 5HT1A agonism has been shown to increase dopamine release in this area of the brain and is also hypothesized to treat both negative and cognitive symptoms of schizophrenia.4 In addition to cariprazine, clozapine, ziprasidone, aripiprazole, and lurasidone also display partial 5HT1A agonist properties.3,5 Cariprazine has also demonstrated positive preliminary results for the treatment of acute mania in a phase III clinical trial. Phase II clinical trials are also being conducted evaluating cariprazine for use in bipolar depression and as adjunct therapy to antidepressants for major depressive disorder.6 

An alternative to the dopamine hypothesis of schizophrenia is the glutamate hypothesis, which developed in the 1980s in response to low glutamate levels observed in the CSF of patients with schizophrenia.3 This hypothesis attributes the development of schizophrenia to a hypofunctioning of the glutamatergic system and is further supported by the finding that NMDA receptor antagonism, observed with phenylcyclidine and ketamine, result in schizophrenia-like symptoms. Glycine is an essential co-transmitter on the NMDA receptor and channel opening only occurs in the presence of both glutamate and glycine. Glycine transporter inhibitors are a therapeutic target for some newer agents, including RG1678. Enhancing glycine levels via inhibition of the glycine transporter may improve both positive and negative symptoms of schizophrenia and increase NMDA receptor function. A multi-center, double-blind, parallel group phase II study of RG1678 as add-on treatment to patients stabilized on antipsychotics, with residual negative or disorganized thought symptoms, found a statistically significant difference in negative symptoms from baseline to week 8 on the negative subscale of the PANSS. Phase III studies are currently investigating the use of RG1678 as add-on therapy to antipsychotics for patients with negative or residual positive symptoms of schizophrenia. Additional antipsychotic drug targets currently being investigated include 5HT2C agonists, ampakines, metabotropic glutamate receptor agonists (mGluR2/3), alpha-7 nicotinic receptor agonists, phosphodiesterase 10a inhibitors (PDE10a), 5HT6 antagonists, and H3 antagonists. The future holds many exciting opportunities for the development of novel antipsychotic agents that combat negative and cognitive symptoms of schizophrenia.

The December issue of the Mental Health Clinician is dedicated to providing an update on psychiatric and neurologic medications that have recently entered the market. In addition to the newer antipsychotics described above (i.e., iloperidone, asenapine, lurasidone), this issue will also review vilazodone (Viibyrd®), a new antidepressant, as well as new anticonvuslants or formulations, including ezogabine (Potiga™), clobazam (Onfi), and gabapentin enacarbil (Horizant™). An article describing CPNP members' experiences with Zyprexa Relpevv is also included in this issue. Happy holidays and happy reading to all!

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