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Indian Journal of Pharmacology, Vol. 43, No. 2, March-April, 2011, pp. 105-112 Educational Forum Newer molecules in the treatment of schizophrenia: A clinical update Abhishek Ghosh, Kaustav Chakraborty, Surendra Kumar Mattoo Department of Psychiatry, Postgraduate Institute of Medical Education and Research, Chandigarh - 160 012, India Correspondence Address: Surendra Kumar Mattoo, Department of Psychiatry, Postgraduate Institute of Medical Education and Research, Chandigarh - 160 012, India, skm_ddtc@glide.net.in Date of Submission: 30-Apr-2010 Code Number: ph11034 DOI: 10.4103/0253-7613.77334 Abstract Schizophrenia is a heterogeneous psychiatric disorder in which multiple neurotransmitter systems have been implicated. Increased and decreased dopamine transmission in the subcortical meso-limbic and meso-cortical systems is closely linked to the "positive" and "negative" symptoms of schizophrenia, respectively. Important roles have also been found for serotonin and acetylcholine, both of which are closely linked to dopamine. An abnormality in glutamate functioning involving N-methyl-D-aspartic acid as well as other receptor subtypes may underlie the dopamine dysfunction observed in schizophrenia. Since the discovery of chlorpromazine in 1952, researchers have been developing new molecules targeting various neurotransmitter systems to maximize their efficacy and tolerability. The advancements in molecular genetics have opened up new horizons to manipulate the post-receptor protein cascade and gene expression. Although the magic-wand still eludes us, the newer molecules hold a lot of promise in this condition.Keywords: Drugs, molecules, neurotransmitters, novel, schizophrenia Introduction Schizophrenia is a neurodevelopmental psychiatric disorder with etiology spanning both genetic and environmental factors. It affects 1% of the population and ranks among the top 10 causes of disability worldwide. The core features of schizophrenia include "positive," "negative," "cognitive," and "affective" symptoms. The positive symptoms (e.g., agitation, delusions, hallucinations and grossly disorganized behaviour) are easily identified, are more likely to lead to hospitalization, and have been used as main determinants of illness outcome. The negative and cognitive symptoms, although less florid, are usually much more pernicious. While positive symptoms are most amenable to treatment, there is no effective treatment available for "negative" and "cognitive" symptoms. [1] This review critically appraises the first- and second-generation antipsychotics (APs) already in use. The recent advances in the psychopharmacology of schizophrenia are also summarized. These drugs act on complex mechanisms involving neuroreceptors, post-receptor protein cascades, and gene expression. Data Search Methodology The data search strategies used included electronic databases as well as hand-search of relevant publications or cross-references. The electronic search included PUBMED, Google Scholar, PsychINFO, etc. Cross-searches of electronic and hand search key references yielded other relevant material. The search terms used, in various combinations, were schizophrenia, management, treatment, novel, molecules, drugs, preclinical, clinical, pipeline, and trials. Data Review Methodology The data inclusion for this review was guided by the following principles. We included studies conducted after 1990. We were over-inclusive and did not restrict our data inclusion by any standardized methodology. The intent was to include as much research and as many aspects as possible on the newer molecules in the treatment of schizophrenia. Wherever applicable, the strengths and the limitations of the cited research are also discussed. Evolution of AP Drugs Psychotic disorders have been recognized since ancient times and there have been ongoing attempts at discovering effective treatments for these. The modern era of treating psychosis evolved through insulin coma, camphor coma, electroconvulsive therapy, and antipsychotic medications (AP) beginning with reserpine and culminating in the introduction of chlorpromazine (CPZ) in 1952. CPZ and other first-generation antipsychotics (FGAs) that followed had a heterogeneous receptor-binding profile and low potency, requiring higher doses for a therapeutic response. Subsequent development of selective D2 antagonists like haloperidol and fluphenazine led to high potency/lower dose APs. In 1990s the second-generation antipsychotics (SGAs) were introduced. Their development was based on clozapine, which had a substantially different receptor-binding profile, resulting in some efficacy in refractory patients, and lower motoric side effects (MSE) like extrapyramidal effects (EPS), neuroleptic malignant syndrome (NMS), and tardive dyskinesia (TD). The SGAs have virtually become the first treatment of choice for schizophrenia, but they have not lived up to high expectations based on initial gratifying experience with clozapine in treatment refractory cases. Even though they carry an almost negligible risk of MSE compared to FGAs, their efficacy in treating negative, cognitive, and depressive symptoms is only modestly better than that of FGAs. [2] Another systematic review and meta-analysis of randomized controlled trial (RCTs) comparing SGAs concluded that for positive (not negative) symptom reduction, olanzapine was the most efficacious SGA, risperidone was superior to quetiapine and ziprasidone, and clozapine was superior to zotepine and, in doses >400 mg/day, to risperidone. [3] A critical appraisal of available AP drug Despite the short-term efficacy of APs, the overall treatment outcome remains poor with the majority of patients with schizophrenia experiencing poorer quality of life due to relapses, enduring symptoms, and deficits in cognitive and psychosocial functioning. While RCTs seem to suggest that SGAs significantly improve cognition, there is some evidence that the improvements may, at least in part be due to practice effects. These realizations have led to an initiative in the United States to facilitate the development of newer APs focusing on mitigation of cognitive impairments in schizophrenia (Measurement and Treatment Research to Improve Cognition in Schizophrenia, or MATRICS). This project has identified three drug mechanisms for particular attention: cholinergic, dopaminergic, and glutamatergic. Clinical efficacy trials are currently underway evaluating potential cognitive-enhancing agents. [4] Compared to FGAs, the SGAs induce less of MSE, particularly the TD. Many FGAs and SGAs like risperidone, amisulpride, and paliperidone induce hyperprolactinemia which may be either asymptomatic, or associated with clinical effects such as gynecomastia, galactorrhea, menstrual irregularities, and sexual dysfunction. Most SGAs (and some FGAs) are also associated with weight gain and metabolic disorders including glycemic dysregulation and an atherogenic lipid profile. These metabolic disorders are in turn a risk factor for microvascular and macrovascular diseases, leading to increased risk of morbidity and mortality. [5] Thus, there is a need for a new generation of APs free of the listed drawbacks. In the following section we will consider such newer APs being developed for marketing in the near future, focusing on their efficacy, adverse effects, and pharmacodynamic and pharmacokinetic profiles. Third-generation AP drug To find better alternatives to the existing APs, novel receptors are being targeted to develop the so-called third-generation APs. Glutamatergic Agents NMDA (N-methyl-d-aspartic acid) receptor---GLY site agonists NMDA receptors, the most complex ionotropic GLU (glutamate) receptors, are a primary drug development target for schizophrenia treatment. In addition to the recognition site for GLU, a NMDA receptor contains a neuromodulatory site for glycine (GLY) that affects channel open time and desensitization rate in the presence of agonist (GLU), but does not itself induce channel opening . A first-generation approach to potentiate NMDA receptor-mediated neurotransmission in vivo has been the administration of the amino acids GLY and d-serine (DSR), which serve as endogenous modulators of the NMDA receptor complex. A more recent approach has been the targeting of amino acid transporters that regulate amino acid levels in vivo, analogous to the use of selective serotonin reuptake inhibitors, rather than exogenous tryptophan administration to modulate brain serotonin levels in depression. Trials in schizophrenia have been conducted with the endogenous ligands GLY and DSR which function as full agonists at the GLY site. Both GLY and DSR cross the blood--brain barrier and so can be administered systemically. But as they are extensively metabolized in the periphery, large doses must be given (rodents 0.8-1.6 g/kg and humans 0.4 g/kg i.v. or 0.8 g/kg p.o.). [6] DCS (d-cycloserine), generically an antitubercular drug, cross-reacts with the NMDA receptor GLY site to act as a partial agonist with a 30--60% of the efficacy of GLY or DSR. [6] These molecules have been tested clinically as adjuvant to conventional neuroleptics, clozapine, olanzapine, and risperidone. The effective dose levels were 30--60 g/day for GLY, 2.1 g/day for DSR, and 50 mg/day for DCS. [7] DCS had a narrow therapeutic window: doses <50 mg/day were ineffective but doses >100 mg/day caused symptom exacerbation due to emergent NMDA receptor antagonist effects. A Cochrane meta-analysis of the first 16 RCTs with GLY, DSR, and DCS (n=343) concluded that GLY and DSR (but not DCS) were effective in reducing negative symptoms of schizophrenia. [7] The cognitive and positive symptoms responded when the full agonists GLY and DSR were added to FGAs, but long-term treatment response is unknown. The addition of GLY and DSR to clozapine showed no significant symptom change. [7] On the other hand, the addition of DCS to clozapine resulted in a worsening of negative symptoms. However, the US National Institute of Mental Health (NIMH) multi-centre study (CONSIST) comparing GLY and DCS failed to document any significant therapeutic benefit of either GLY or DCS. [8] Glycine transporter inhibitor Similar to clozapine, a selective glycine T1 inhibitor increased expression of c-fos in nucleus accumbens and prefrontal cortex but not in caudate nucleus. In studies in mice, reversal of the PCP-induced but not amphetamine-induced locomotor activity has been documented along with reversal of pre-pulse inhibition (PPI) deficits in neonatal ventral hippocampally lesioned rats. In one study, 65 risperidone-treated in-patients with acute exacerbations of schizophrenia were given a 6-week, randomized, double-blind trial (DBT) comparing adjuvants sarcosine (a glycine transporter inhibitor) 2 g/day, DSR 2 g/day, and placebo. The sarcosine group showed significantly more symptoms improvement than the other two groups. [9] In a 6-week, controlled trial with chronic schizophrenia patients, sarcosine 2 g/day adjuvant treatment led to 17% (P < 0.0001), 14% (P < 0.0001), and 13% (P < 0.0001) reductions in positive, negative, and cognitive symptoms, respectively, without inducing any significant side effects. [9] AMPA (α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate) receptor modulators AMPA receptor modulators may provide an alternative to NMDA receptor-GLY site stimulation for enhancing NMDA receptor function and facilitating glutamatergic neurotransmission. A distinct class of agents, developed to enhance glutamatergic function, is the AMPA-positive modulators termed AMPAkines, a family of compounds that act by increasing the peak and duration of GLU-induced AMPA receptor-gated inward currents. AMPAkines enhance glutamatergic activity in the cortex, stimulate memory-dependent processing in animal models, and improve, acutely, memory capabilities in both young and aged humans without any apparent serious side effects. L-(Quinoxalin-6-carbonyl) piperidine (CX-516) is the first AMPAkine to reach Phase I trials in schizophrenia. In a pilot DBT, patients taking clozapine were randomized to receive CX-516 ≤900 mg t.i.d. or a placebo for 4 weeks. Significant CX-516-induced improvements in cognitive and negative symptoms were reported in 18 schizophrenia patients participating in the study. [10] One patient had a possible treatment-related side effect, hypertension. In another small study (n=8), CX-516 ≤ 1200 mg t.i.d. was assessed as monotherapy with no clear benefit for schizophrenia patients partially refractory to traditional neuroleptics. [11] A more powerful compound with improved pharmacological properties (CX-717) is being examined as adjuvant treatment for schizophrenia in a larger study. The NIMH-sponsored Treatment Units for Research on Neurocognition in Schizophrenia (TURNS) has recently selected the AMPAkine CX-619/ORG-24448 for testing as a medication for enhancing neurocognition in schizophrenia. [12] mGluR (metabotropic glutamate receptors) modulators mGluRs are G protein-coupled-receptors that include eight subtypes termed mGluR1-8. Group I receptors mainly potentiate both presynaptic GLU release and postsynaptic NMDA neurotransmission, with mGluR5 receptors showing significant co-localization with NMDA receptors in rodents. Groups II and III receptors generally serve to limit GLU release, particularly during conditions of GLU excess. Thus, group I agonists or positive modulators are expected to stimulate NMDA receptor-mediated neurotransmission, and group I antagonists to inhibit it. In contrast, group II/III agonists or positive modulators are expected to inhibit presynaptic GLU release. Preclinical studies assessed the ability of group I (mGluR1, mGluR5) agonists to reverse effects induced by amphetamine, PCP, and other psychotomimetics. The mGluR5 agonist 2-chloro-5-hydroxyphenylglycine reversed PPI-disruptive effects of amphetamine in rodents. [13] The effect of group II agonists on prefrontal glutamatergic hyperactivity led to the hypothesis of these agents being therapeutic for persistent cognitive deficits in schizophrenia. However, the extent of psychotomimetic effects of PCP on alterations in glutamatergic versus dopaminergic neurotransmission is not known. [14] The mGluR2 agonists may also help to clarify the patho-physiological mechanisms in schizophrenia. Overall, compared to NMDA receptor-based approaches, mGluRs modulators are in relatively early stages of development as potential drugs for schizophrenia. Ion-channel blockers/GLU release inhibitors From this group lamotrigine and riluzole, medications for epilepsy and amyotropic lateral sclerosis (ALS), respectively, are being tested for schizophrenia clinically because of their ability to inhibit excessive presynaptic GLU release. Lamotrigine, chemically unrelated to any currently available anticonvulsant medications, is effective for treating affective disorders. It reduces GLU release by blocking voltage-dependent ion channels (Na, P, and N-type calcium, and outward K channel). Thus, pretreatment with lamotrigine reduces ketamine-induced psychosis, negative symptoms, and dissociation-like perceptual alterations. In two animal models, it showed efficacy indicating the therapeutic value in schizophrenia. In three open-label series, adjuvant treatment with lamotrigine (100--300 mg/day) induced significant (≤75%) symptom reductions in clozapine-maintained, treatment-resistant patients. [15] In a 14-week RCT with 34 males addition of lamotrigine ≤ 200 mg/day to clozapine significantly improved positive and general psychopathology symptoms. [16] In another study, an addition of lamotrigine 400 mg/day to FGAs/SGAs for 10 weeks caused significant mean reductions in positive (-42%, P <0.03) and general psychopathology (-36%, P <0.03) symptoms but not in the negative symptoms. [17] Riluzole which inhibits voltage-dependent Na+ channels, resulting in decreased GLU release, is US-FDA approved as a neuroprotective agent for ALS. Studies with this drug have reported beneficial effects in depression and obsessive-compulsive disorder. Clinical trials for its effectiveness in schizophrenia are warranted. Cholinergic agents Alpha-7 nicotinic receptor partial agonists Alpha-7 nicotinic receptor is one of the nicotinic acetylcholine receptors (nAChRs), a large family of ligand-gated ion channels. In patients with schizophrenia preclinical, genetic, and human postmortem studies suggest reduced function of alpha-7 receptors, which is associated with deficits in various psycho-physiological measures like sensory inhibition of the P50 auditory-evoked response, auditory sensory gating, and voluntary smooth pursuit eye movements. [18] Nicotine is known for transient cognitive enhancing clinical effect in schizophrenia. Concurring with this fact, DMXBA, a partial agonist at the alpha-7 nicotinic receptor was noted to enhance auditory sensory gating in animal models. This led to speculation that DMXBA might improve P50 auditory gating and cognition in schizophrenia. [19] Galantamine, another alpha-7 nicotinic receptor modulator, is in Phase II clinical trials for selective benefits in processing speed and verbal memory in patients with schizophrenia. However, addition of galantamine to AP treatment reportedly made no change in the cognitive function or state of psychopathology in schizophrenia. [20] Another selective agonist at the neuronal nicotinic receptor, TC-1734 (renamed AZD3480), has been shown to produce significant enhancement of several cognitive measures (attention and episodic memory), and is in Phase II-b trials for the treatment of cognitive deficits in schizophrenia. Two other members of this family, MEM 3454 and PH-399733, are also in Phase II clinical trial. [21] Similarly, alpha4 beta2 nAChR partial agonist Varenicline, meant for treating nicotine dependence, is being evaluated for cognitive dysfunction in schizophrenia. Muscarinic M1 agonists Post-mortem and neuroimaging studies in schizophrenia show a significant decrease of muscarinic receptor density, especially for M1 subtype, in the frontal cortex, basal ganglia, and hippocampus. M1 receptor knockout mice show specific behavioral changes that are typical in animal models of schizophrenia. Conversely, administration of selective M1 receptor antagonists produces significant cognitive impairment. Xanomeline, a muscarinic agonist with high M1 activity, is effective in the cognitive and psychotic symptoms of patients with Alzheimer′s disease (psychotics > cognitive). This drug selectively inhibits the firing of meso-limbic dopamine cells even after acute administration and would have a faster onset of action compared to current APs and would not induce extrapyramidal side effects. [22] Thus, preclinical data are suggestive of an AP-like profile of this drug that may become available in transdermal patches, with less adverse effects. Serotonergic (5-hydroxytryptamine, 5-HT) agents 5-HT1A, 5-HT2C, 5-HT6, and 5-HT7 receptors are the focus of new research. Most SGAs bind strongly to 5-HT2A receptors. However, a selective 5-HT2A receptor antagonist was found not to be effective as an AP. 5-HT1A receptors are activated by 5-HT2A antagonism, suggesting that combining 5-HT1A agonism with D2 antagonism may confer therapeutic advantages. 5-HT2C receptor agonists inhibit DA release in the meso-limbic and meso-cortical pathways without having an effect on nigrostriatal pathways, suggesting possible AP activity without motor side effects for compounds acting on these receptors. The 5-HT4, 5-HT6, and 5-HT7 receptors may also be important, particularly in reference to the cognitive deficits in schizophrenia. [23] 5-HT2 antagonists/inverse agonists Greater 5-HT2 versus D2 receptor antagonism distinguishes SGAs from FGAs. Advantages of inverse agonism over antagonism can attenuate basal constitutive signaling activity. Pimavanserin, eplivanserin, and pruvanserin which represent 5-HT2A receptor inverse agonists are currently in Phase II clinical trials as add-on strategies. Preliminary results from a Phase II evaluation of Pimavanserin showed significant improvement in AP efficacy with low-dose risperidone compared to placebo but not with low-dose haloperidol. [24] 5-HT 6 antagonists Polymorphisms of the 5-HT6 receptor have been implicated in both schizophrenia and dementia. Clozapine exhibits 5-HT6 receptor antagonist property responsible for its unique AP efficacy. GSK-742457, a 5-HT 6 antagonist, is currently in Phase II clinical trials. [25] 5-HT2C receptor-selective agonist 5-HT2C receptor agonists selectively decrease meso-limbic DA. In animal models of schizophrenia a molecule of this class, WAY-163909, has been shown to decrease apomorphine-induced climbing and phencyclidine-induced locomotor activity. Like an atypical AP, it selectively decreased extracellular levels of DA in the nucleus accumbens without affecting the striatum; additionally, it had a more rapid onset of action. [23] H3R (histamine receptor subtype 3) inverse agonist As a presynaptic autoreceptor in cerebral neurons H3R has highest densities in the basal ganglia, hippocampi, cortical, and striatal areas. Classical H3R inverse agonist thioperamide has shown enhanced cognitive performance, AP-like characteristics, and improvement of short-term memory in rodents. Other agents being studied from this class include ABT-834 (for ADHD) and ABT-239 (for undisclosed cognitive disorders). ABT-239, halted in Phase I due to unfavorable cardiovascular effects in monkeys, had shown excellent potency and efficacy in rodent models for cognition and schizophrenia. It increased the release of acetylcholine and dopamine in the frontal cortex and hippocampi and did not bind CYP enzymes to a great extent. [26] An oral H3R inverse agonist (GSK-189254) significantly improved performance of rats in various cognition tests, including passive avoidance, water maze, object recognition, and attention-set shift. [27] Two other H3R inverse agonists (GSK-334429 and GSK-207040; latter being structurally related to GSK-189254) have also been studied. In animal models, the latter significantly enhanced object recognition memory and attenuated isolation rearing induced deficits in PPI but it did not reverse amphetamine-induced increase in locomotor activity. All these support the potential of H3R antagonism to treat the cognitive and sensory gating deficits of schizophrenia although the therapeutic utility for positive symptoms is doubtful. [26] Newer dopaminergic and dual acting (serotonergic and dopaminergic) agents Dopamine D2 receptor antagonist and 5-HT1A receptor agonist (SSR181507 and SLV3313) Both dopamine D2 receptor antagonist and 5-HT1 A receptor agonist (SSR181507 and SLV3313) have a unique neurochemical and electrophysiological profile that is linked to dual properties which are expressed in the same dose range. It is hypothesized that these drugs should be without the liability of extrapyramidal side effects and be efficacious against positive, negative, and cognitive symptoms of schizophrenia, and schizophrenia-associated mood and anxiety disorders. [28] D2/D3 antagonist, 5-HT1A agonist, and D4 partial agonist properties (F15063) In rodent, model F15063 potently reversed methylphenidate-induced stereotyped behaviors and attenuated apomorphine-induced PPI deficits without inducing catalepsy. So it should have low EPS liability, complemented by a favorable profile for negative symptoms and cognitive deficits of schizophrenia. [29] l-stepholidine As a naturally occurring dopamine receptor D1 agonist and D2 antagonist it should control psychosis and treat cognitive symptoms by enhancing cortical dopamine transmission. In animal studies, it is effective in reducing amphetamine and phencyclidine-induced locomotion as well as conditioned avoidance response, with catalepsy and prolactin elevation as the main side effects. This action profile is like that of an atypical AP. [30] Asenapine Asenapine, being developed for treating schizophrenia and bipolar disorder, is in the preregistration phase with the FDA. It shows high affinity for and behaves as a potent antagonist at serotonin receptors (5-HT1A, 5-HT1B, 5-HT2A, HT2B, 5-HT2C, 5-HT5, 5-HT6, and 5-HT7), adrenoceptors (α1, α2A, α2B, and α2C), DA receptors (D1, D2, D3, and D4), and histamine receptors (H1 and H2). It displays 5-HT1A partial agonistic activity with region-specific and dose-dependent effects on ionotropic glutamatergic receptor subtypes in the rat forebrain, predicting AP activity with low motor side effect potential and a possible pro-cognitive effect. [31] In a 6-week Phase II RCT, asenapine 5 mg b.i.d. was assessed against placebo b.i.d. and risperidone 3 mg b.i.d. in 174 patients with acute schizophrenia. [32] Mean improvements on Positive and Negative Symptom Scale (PANSS) total, positive, negative, and general psychopathology subscale scores and Clinical Global Impression---Severity (CGI-S) were all significantly greater with asenapine than with placebo (P < 0.005, P = 0.01, P = 0.01, P < 0.005 and, P < 0.01, respectively). Adverse event (AE) rates were similar for asenapine and placebo, while substantial weight gain and prolactin elevation were observed with risperidone. [32] In another 6-week RCT, 450 subjects with acute schizophrenia were compared using fixed doses of asenapine 5 or 10 mg b.i.d. or placebo or haloperidol 4 mg b.i.d. At end point, asenapine 5 mg b.i.d, but not 10 mg b.i.d., was significantly better than placebo for PANSS total score reduction. Akathisia was the only dose-related AEs. The motor AEs were higher with asenapine (15 and 18% at 5 and 10 mg twice daily, respectively) compared with placebo (10%), but lower than that with haloperidol (34%). [33] A long-term study on safety assessed 1219 patients with acute exacerbation of schizophrenia or schizoaffective disorder. AEs in both treatment groups were insomnia, worsening of psychotic symptoms, weight gain, and depression. Both treatment groups showed improvement in motor AEs although EPS-related AEs were more common with asenapine (18%) than with olanzapine (8%). Both treatments had minimal effects on prolactin levels. [34] Iloperidone Iloperidone is an orally well-absorbed 5-HT 2A/D2 antagonist targeting schizophrenia and bipolar disorder that has completed Phase III trials in doses ranging 4-24 mg/day. Phase II and III clinical trials indicate its ability to reduce positive and negative symptoms of schizophrenia, comparable to haloperidol and risperidone. Like ziprasidone and aripiprazole, it has minimal effects on weight and a low incidence of diabetes and EPS. Development of a long-acting depot formulation may improve compliance, in addition to a generally low AE profile. The two biggest factors supposed to predict its clinical success are: QTc interval changes and any novel effect it has in personalized medicine in regard to response to specific genotypes in schizophrenic patients. [35] Norclozapine Clozapine undergoes extensive hepatic metabolism leading to two major metabolites, norclozapine (N-desmethylclozapine-NDMC) and clozapine N-oxide. Norclozapine has a unique AP efficacy in vitro as a 5-HT2 antagonist and as a partial agonist to dopamine D2 and muscarinic receptors. Despite high expectations, results from a recent 6-week, multicentre, placebo-controlled, phase II, DBT of norclozapine were disappointing. The two doses used (100 or 200 mg twice daily) did not demonstrate efficacy as measured by PANSS total score and PANSS subscales and CGI scale, respectively. Most common AEs were dose-related hypersalivation, tachycardia, and dyspepsia. Also, importantly no significant decreases in neutrophil counts were observed. [36] Bifeprunox The drug has partial agonist activity at D2, D4, and 5-HT1A receptors, and antagonism at D3 receptors. In a multicentre, 6-week, randomized, placebo controlled, risperidone referenced trial Casey et al. showed that Bifeprunox 30 mg produced a significant difference from placebo in the change in the PANSS total score. [37] For long-term efficacy and safety of bifeprunox, a 6-month, DB, RCT parallel-group, placebo-controlled, fixed-dose study showed patients receiving bifeprunox 20 or 30 mg/day took significantly (P = 0.008 and P = 0.006, respectively) longer time to deterioration compared to placebo. [38] A decrease in weight was greater with bifeprunox compared to placebo. Non-fasting cholesterol, glucose, and triglyceride levels were also lower with bifeprunox 30 mg and 40 mg/day. Bifeprunox was also associated with a lower incidence of EPS than risperidone. [38] Omega-3 fatty acids Decreased n-3 fatty acid levels have been reported in patients with depression, schizophrenia, and Alzheimer′s disease. Recently, eicosapentaenoic acid (EPA) has been used to treat several psychiatric and neurodegenerative diseases due to its anti-inflammatory and neuroprotective effects. A case study showed EPA treatment at 2 g/day to improve schizophrenia in terms of Schedule for the Assessment of Positive Symptoms (SAPS) and the Schedule for the Assessment of Negative Symptoms (SANS). SAPS and SANS scores decreased from 46 to 7 and 16 to 3, respectively by months 1 and 2. [39] Peet et al. evaluated the efficacy of omega-3 fatty acids in two studies using the PANSS. [40] In one study, 45 patients were randomized to EPA, DHA (docosahexaenoic acid), and placebo groups, and in the other 26 patients were given EPA 2 g/day as sole treatment. The EPA group showed greater improvement compared to placebo and DHA on the PANSS-positive symptom score. All placebo group patients had to be placed on medication and 6/14 patients in EPA group stayed off other drugs entirely. Those who took medications did so for < 1 month on average. Only minimal AEs such as fishy eructation or breath, and gastrointestinal effects such as diarrhea were reported with EPA treatment. Cannabinoid agents The endogenous cannabinoid system, that includes the G protein coupled receptors CB1 and CB2, has been implicated in the etiopathogenesis of schizophrenia. Increased cerebrospinal fluid levels of anandamide (an endogenous cannabinoid) found in patients with schizophrenia seems to substantiate this. The cannabinoid CB1 gene alters the behavioral effects of the NMDA antagonist phencyclidine. Rimonabant, a selective cannabinoid CB 1 receptor antagonist, reduces stimulant-induced hyperactivity in rats. SR14176 and AM251, which are cannabinoid CB1 receptor antagonists, reverse deficits of sensorimotor gating induced by phencyclidine but were not beneficial against placebo. AVE1625, a selective cannabinoid CB 1 antagonist, has gone on to Phase II clinical trial as an add-on to SGA.[41] Neuropeptides Neurotensin (NT) agonists NT receptors have been potential targets for treatment of various neuropsychiatric diseases including schizophrenia. NT69L, the most widely studied, is in early stages of preclinical toxicology testing. It crosses the blood--brain barrier to cause effects similar to that of endogenous NT and produces AP effects without extrapyramidal AEs. Rodent studies show it causes anti-nociception, hypothermia, and hypotension. The hypotensive effect observed in rodents is expected to be tolerated on continued use. Initial clinical testing in humans may start soon. [42] Neurokinin-3 (NK3) antagonists Neurokinin receptors, said to modulate the activity of dopamine neurons in the ventral tegmentum and pars compacta of substantia nigra, may be involved in schizophrenia. SB-223412 (Talnetant), a highly selective NK3 receptor antagonist, has undergone three Phase II DB, PC, RCTs, evaluating its efficacy in the treatment of positive and negative symptoms of schizophrenia. [43] Cholecystokinin Open-label studies indicated ceruletide, a cholecystokinin analog, to be possibly effective in negative symptoms of chronic refractory schizophrenia in a dose of 0.3-2.0 mg/kg, i.m. Five of seven DB studies in AP-medicated chronic schizophrenia reported ceruletide to have no significant AP effect. [44] Heterogeneity of the patient population has been alluded to as contributing to the inconsistent results of the later studies. Abdominal discomfort is a prominent AE occurring 30--60 min after ceruletide administration and disappearing within a few minutes. Ceruletide disappears from the blood within 1 h after administration thereby questioning the long-lasting AP effect. Other molecules Sigma receptor antagonist Rimcazole, a carbazole derivative that acts partly as a sigma receptor antagonist, was introduced in 1980s hypothesizing it to be a novel AP with an improved side effect profile. Subsequent clinical trials compared it to placebo and CPZ, and demonstrated its lack of efficacy in schizophrenia. Though EPS was low, neurological side effects in the form of EEG abnormality, GTCS, muscle fasciculation were seen in higher doses (550--600 mg/day). [45] COX-2 inhibitors COX-2 is known to influence the balance between types 1 and 2 immune responses. Celecoxib is an NSAID with highly selective COX-2 inhibitor property. An 8-week, DB PC trial investigating celecoxib as an add-on to risperidone in the treatment of chronic schizophrenia demonstrated significant superiority of the combination over risperidone in the treatment of positive and general psychopathology symptoms. This study has been through a Phase II RCT. [46] Alpha 2 agonists Dysfunction of the prefrontal cortex, critical for working memory, is implicated in schizophrenia. Noradrenaline plays a significant role through its actions at alpha 2a noradrenergic receptors in this type of memory. Guanfacine is a recently developed selective alpha-2 agonist demonstrating preclinical efficacy in reversing working memory deficits. Tried as an adjunctive treatment to SGAs for cognitive dysfunction in schizophrenia, it is in the Phase IV clinical trial. [47] GABA-A receptor modulation Deficits in working memory and cognitive control in schizophrenia are associated with impairments in prefrontal cortical function. Abnormalities are thought to reflect a deficiency in the synchronization of pyramidal cell activity that is partly dependent on gamma-aminobutyric acid (GABA) neurotransmission. RCT comparing the efficacy MK-0777 (a benzodiazepine-like agent with selective activity at GABA-A receptors containing α2 or α3 subunits) found that outcome measures such as the brief psychiatric rating scale (BPRS) score was not altered, but N-back, AX continuous performance test, and neuropsychological batteries were improved. [48] Adenosine 2A receptor agonist Strong functional antagonistic interaction between adenosine 2A receptor and dopamine D2 receptor has been found. So adenosine 2A receptor agonist CGS-21680 may have potential as AP efficacy. They manifest functional antidopaminergic effect without production of EPS in rats and monkeys. [49] Conclusion Schizophrenia is a complex disease. There is unlikely that a single molecule, be it a neurotransmitter, receptor or enzyme "causes" schizophrenia. Rather, different transmitters interact in a complex web to produce specific symptoms and phenomena, whose proximate cause may lie in processes such as aberrant brain development. Increased dopamine transmission in the subcortical meso-limbic system is closely linked to the positive symptoms of schizophrenia, perhaps by disrupting a "filter" for sensory information. Conversely, a decreased dopamine transmission in the meso-cortical system, connecting the midbrain and the cortex, may be linked to negative and cognitive symptoms. Important roles have also been found for serotonin and acetylcholine, both of which are closely linked to dopamine. All these molecules are targets for antipsychotic drug action. Other molecules, such as neuropeptides, probably have smaller but no less important roles. An abnormality in glutamate functioning may underlie the dopamine dysfunction seen in schizophrenia. Initial breakthrough with the discovery of CPZ was a huge step forward, but subsequent advances have been small. Modest tolerability and efficacy advantages may translate into meaningful benefits for individual patients in terms of functionality and quality of life but a "magic wand" for this devastating heterogeneous disease entity is still to come. Perhaps one or more of the newer molecules that are in developmental phase will provide the much-needed breakthrough. Two factors are likely to hamper target identification and validation. Those are the lack of a stable objective phenotype associated with disease pathology and the absence of the Mendelian form of disease. Recent advancements in molecular genetic studies may help in better understanding of the etiopathogenesis of schizophrenia and open the gateway for newer drug development. References
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