RECENT ADVANCE IN TREATMENT OF SCHIZOPHRENIA

• Schizophrenia is recognized as a heterogeneous disorder linked to multiple genes which individually exert relatively small effects and which are believed to interact with numerous environmental factors.

• Phenotype is similarly heterogeneous, composed of at least four or five distinct symptom clusters, including psychotic symptoms, disorganization, negative symptoms, cognitive deficits, and affective symptoms . The pattern of symptom expression is diverse within patient samples.

• Medications also differ in patterns of symptom response. Future advances in drug development first require identification of subgroups of patients that share biological defects in common and may also take into account different pathogenic mechanisms associated with different stages of the disease.

• Pharmacological interventions that target specific symptoms may be necessary rather than continued attempts to treat the full syndrome with a single agent.

• The classic pharmacological model, stimulant intoxication, produces delusions and hallucinations that closely resemble psychotic symptoms of schizophrenia and generally can be fully attenuated by dopamine antagonists. Stimulant intoxication is less informative for other symptoms of schizophrenia.

• A subgroup of schizophrenia patients exhibit increased dopamine release which positively correlates with response to conventional antipsychotic medication

• An additional pharmacological challenge of interest to schizophrenia drug development involves infusion of noncompetitive antagonists that block the glutamatergic-NMDA gated channel. Drugs such as phencyclidine (PCP) and the lower-affinity dissociative anesthetic, ketamine, produce a broad spectrum of schizophrenia-like symptoms in normal subjects, including psychosis, negative symptoms and memory deficits. Ketamine also exacerbates symptoms in schizophrenia patients who have been stabilized on haloperidol—an effect that is blocked by clozapine .

• Furthermore, the abnormality in amphetamine-induced striatal dopamine release characteristic of some patients with schizophrenia can be reproduced in normal subjects with ketamine.—all of which demonstrate preferential response to atypical antipsychotics compared to conventional agents

• Several genes with biologically relevant functions recently have been linked preliminarily to schizophrenia.

• For example, a gene on chromosome 8p, associated with expression of neureglin, has been linked to schizophrenia. Neureglin plays a role in brain development, particularly the expression of NMDA receptors. Transgenic mice heterozygous for the neureglin allele express 16% fewer NMDA receptors compared to normal mice, and exhibit hyperactivity and abnormal PPI; the abnormal behaviors respond to clozapine.

• In a related finding, Mohn and colleagues produced transgenic mice with an approximately 95% reduction in functional NMDA receptors (by deletion of the NMDAR1 subunit) and found that mice exhibited hyperactivity, sterotypies, and social isolation. Hyper-activity and stereotypy improved with haloperidol, whereas only clozapine improved social withdrawal.

• In addition, two genes involved in expression and activation of D-amino acid oxidase (DAAO) have also been linked to schizophrenia. DAAO metabolizes D-serine, a neurotransmitter believed to play an important role in activating the glycine co-agonist site of the NMDA receptor. It is hypothesized that a polymorphism that results in heightened activity of DAAO might lower brain concentrations of D-serine, decrease activation of NMDA receptors, and hence place individuals at risk for schizophrenia. An additional gene is involved in expression of catecholamine-O-methyl transferase (COMT), an enzyme that metabolizes intrasynaptic dopamine . While the presence of a polymorphism that would increase COMT activity and decrease dopamine concentrations has only a modest impact upon risk, COMT status does predict phenotypic expression

Dopamine: Future Directions• Preservation of nigrostriatal dopaminergic function remains an important goal for novel

antipsychotics—one that can be partially realized by addition of 5-HT 2A antagonism combined with careful clinical titration of dose, or more successfully by a high dissociation constant for binding to the D receptor, or by partial agonist activity at the D2 receptor.

• It is also possible that atypical agents preferentially bind to D2 and D3 receptors in thalamus and temporal cortex compared to striatum. While atypical agents appear to preserve nigrostriatal function, depolarization blockade of A10 dopamine neurons by atypical agents, which probably is necessary for antipsychotic efficacy, may disrupt cognitive functions associated with the phasic release of dopamine in the prefrontal cortex.

• Efforts to enhance dopaminergic release in prefrontal cortex have included augmentation with psychostimulants. Preliminary evidence suggests that stimulants (amphetamine) may improve prefrontal cortical activation and negative symptoms when administered as a single dose, but repeated dose trials of stimulant augmentation have generally been negative.

• Alternative strategies could include antagonism of dopamine metabolism (COMT or MAOI inhibitors) and augmentation with selective D1 agonists. Clozapine, risperidone and olanzapine have been shown to increase dopamine release in prefrontal cortex, an effect possibly mediated by 5-HT and adrenergic antagonism.

Dopamine: Future Directions• Unfortunately, since the mechanism by which D2 blockade produces

antipsychotic effects remains unclear, it is difficult to design strategies that will preserve or enhance antipsychotic efficacy while minimizing side effects. Targeting D3 receptors is an interesting approach, since a selective D3 antagonist might modulate limbic dopamine activity without affecting ventral tegmental or nigrostriatal neuronal firing.

• Amisulpiride has been reported to preferentially block D3 receptors, to which has been attributed its very favorable clinical profile of efficacy for positive and negative symptoms with minimal EPS. Other, more selective D3 antagonists are currently in development.

• Whether the combination of relatively weak D2 antagonism with relatively strong D1 antagonism, as typified by clozapine, is a model worth replicating in new agents also requires further work. Despite considerable interest in D4 antagonists following the discovery of clozapine’s high affinity for this receptor, trials of selective D4 antagonists have been disappointing.

SEROTONIN• More recently, selective 5-HT2A antagonists have demonstrated the ability to reverse

some behavioral effects of NMDA antagonism, possibly by increasing release of glutamate. However, M100907, a selective 5-HT2A antagonist, was not adequately effective compared with haloperidol in early clinical trials to merit development as an antipsychotic agent. Antagonism of 5-HT2A continues to be a desirable characteristic of antipsychotic agents when combined with D2 antagonist effects.

• Serotonin5-HT1A partial agonists also appear to reverse neurological side effects of D2 antagonists. In an open augmentation study, the 5-HT1A partial agonist, buspirone, improved ratings of EPS and tension when added to haloperidol. Both ziprasidone and aripiprazole exhibit agonist activity at the 5-HT1A receptor—the potential contribution of this activity to clinical response requires study.

• Serotonin-reuptake blockers have also demonstrated efficacy for negative symptoms when added to conventional neuroleptics. This finding has been relatively consistent with fluoxetine and fluvoxamine, but less consistent with other selective serotonin reuptake inhibitors (SSRIs)—the reason for this inconsistency is unclear.

Novel Serotonergic and Dopaminergic Mechanisms

• Iloperidone is a compound in clinical development with SDA properties, but it has even more potent alpha 1 antagonist properties. Mazapertine is a D2 antagonist, but rather than 5HT2A antagonist properties, it has 5HT1A agonist actions. Nemonapride is a D2 (D3, D4) antagonist and 5HT1A agonist as well. The selective 5HT2A antagonist MDL-100,907 was recently dropped from clinical development, as was the 5HT2A/2C antagonist ritanserin in prior years, both for lack of robust efficacy in schizophrenia. However, there remains some continuing interest in both 5HT2C selective agonists and antagonists, several of which are in early development. There are even novel and selective 5HT6 and 5HT7 antagonists in development as well.

Novel Serotonergic and Dopaminergic Mechanisms

• On the dopamine side of the equation, one of the most promising agents in late clinical development is presynaptic D2 autoreceptor agonist. This compound is postulated to exert its antipsychotic actions in a manner far different from serotonin-dopamine antagonism: that is, it may shut off the presynaptic dopamine terminal and stop dopamine release in the mesolimbic dopamine pathway by stimulating presynaptic D2 receptors. The agents CI-1007 and DAB-452 may have a similar mechanism of action.

• Several selective D4 antagonists have been tested in schizophrenia, with generally disappointing results, although some trials are continuing. Such compounds, some more selective for D4 receptors than others, include YM-43611, nemonapride, fananserin, L-745,870, PNU-101,387G, NGD-94-4, LU-111,995, and others.

• Several selective D3 antagonists are being developed, because most known D2 antagonists block D3 receptors as well. It is theoretically possible that pure D3 antagonists, which increase psychomotor behavior in rodents, might activate such behaviors in schizophrenia and thus reduce negative symptoms.

• Other compounds in testing for schizophrenia include D2 modulators-"normalizers" and D2 partial agonists (e.g., terguride, CI-1007, PNU 9639) and D1-like selective antagonists.

NOREPINEPHRINE • Antagonism of postsynaptic alpha 2 adrenoreceptors appears to

enhance release of dopamine in prefrontal cortex and may have cognitive benefits . The selective alpha 1 receptor antagonist, prazosin is also reported to prevent depolarization blockade of A9 dopamine neurons following administration of conventional neuroleptics . While less well studied than D2 and 5-HT2A receptors, adrenergic antagonism is shared by most atypical antipsychotics and may contribute to clinical benefit. It is an intriguing hypothesis that extraordinarily high concentrations of norepinephrine produced by clozapine via unclear mechanisms may reduce sensitivity to environmental stress and hence protect against relapse—an effect possibly also achieved by adrenergic receptor blockade.

GLUTAMATERGIC STRATEGIES• Glutamatergic approaches have received considerable attention in light of reported

abnormalities of glutamatergic receptor density and subunit composition in schizophrenia brain, the production of a broad range of symptoms characteristic of schizophrenia by infusion of NMDA antagonists in normal subjects, and preliminary success with agonists at the glycine site of the NMDA receptor.

• Several placebo- controlled trials have demonstrated improvement of negative symptoms with the addition of the full agonists, glycine and D-serine, or the partial agonist, D-cycloserine, to antipsychotics other than clozapine. Because glycine poorly penetrates the blood-brain barrier, large doses (30–60 g/d) are required to achieve clinical effects. Glycine reuptake inhibitors are currently under development and represent a promising alternative approach. D-Cycloserine, a partial agonist, has produced improvement of negative symptoms over a narrow therapeutic dose range; psychotic exacerbation has been reported at higher doses and in approximately 10% of patients receiving a typical therapeutic dose of 50 mg/d. Glycine and D-serine have demonstrated a broader range of efficacy in preliminary studies; negative symptoms, psychosis, and relatively rudimentary measures of cognitive function have all improved in augmentation studies.

• If found safe, D-serine is particularly attractive since it crosses the blood-brain barrier more readily than glycine, is not removed from the synapse as rapidly by active transport, and has been implicated by recent genetic linkage studies between schizophrenia and genes regulating activity of D-amino acid oxidase.

GLUTAMATERGIC STRATEGIES

• Trials of glycine site agonists added to clozapine have tended to find no clinical improvement and the partial agonist, D-cycloserine, worsened negative symptoms when added to clozapine in two studies . The relative efficacy of glycine site agonists when added to other atypicals is less well studied, although a large clinical trial (the CONSIST study) is currently underway to examine this question.These findings suggest that targeting the glycine site may enhance efficacy of mostantipsychotic drugs, but probably will not improve upon clozapine’s efficacy. This further raises the question of whether clozapine’s superior efficacy may in part reflect activity at the glycine site, mediated by as yet unclear indirect mechanisms.

GLUTAMATERGIC STRATEGIES

• Metabotropic (mGlu) receptor agonists have recently gained attention as a promising new target for antipsychotic development. mGlu receptor ligands have been shown to modulate dopamine neuronal activity in striatum and nucleus accumbens. The group II mGlu receptor agonists have been demonstrated to selectively regulate glutamate release in cortex and hippocampus. In rat models, group II mGlu receptor agonists attenuated phencyclidine behavioral effects but did not prevent disruption of prepulse inhibition.

GLUTAMATERGIC STRATEGIES• A final glutamatergic receptor class which may hold promise as an

area of drug development in schizophrenia is the AMPA receptor. AMPA receptor positive modulators, or “ampakines,” are currently under development. Ampakines augment opening of voltage-dependent NMDA receptors by facilitating early depolarization . In animal studies, ampakines have produced improvements in learning and memory and have acted synergistically when combined with low doses of antipsychotics to attenuate rearing behaviors in response to methamphetamine. In one very preliminary placebo-controlled dose-finding trial, addition of an ampakine to clozapine in 19 schizophrenia subjects was well tolerated and produced some evidence of improvement in memory and attention .

NICOTINE• Alpha-7-nicotinic cholinergic agonists• Nicotinic acetylcholine receptors have also received considerable attention for their

possible role in cognitive deficits of schizophrenia. Nicotine normalizes a sensory gating abnormality measured by the inhibition of P50 evoked response to paired stimuli; this deficit in information processing is found in about 85% of schizophrenia patients and in about half of first degree relatives and has been linked to the alpha 7 nicotinic receptor.

• The gene that expresses the alpha 7 nicotinic receptor, CHRNA7, is decreased by approximately 50% in post-mortem hippocampus from schizophrenia patients compared to normal controls . A polymorphism in the promoter region of the CHRNA7 gene has also been linked to schizophrenia. Pharmacological targeting of the alpha 7 nicotinic receptor is complicated because it is highly sensitive to down-regulation in response to agonists.

• Nicotine transiently normalizes P50 gating deficits, but this effect is lost with repeated dosing. Clozapine uniquely appears capable of improving P50 deficits, apparently via alpha 7 receptors, although the mechanism remains uncertain. It has been suggested that alpha 7 activation by clozapine might be mediated by serotonin 5-HT 3agonist effects which enhance release of acetylcholine.

• A selective alpha 7 agonist, DMXB-A appears to produce sustained improvement of P50 sensory gating with repeated dosing in animal models. Trials in schizophrenia patients will be of great interest to determine whether this compound enhances attention, even in subjects prone to maintain high levels of nicotine from heavy smoking.

MEMBRANE THEORIES OF SCHIZOPHRENIA

• One of the few approaches to schizophrenia treatment that do not focus upon receptor ligands is based on the conceptualization of schizophrenia as a brain lipid disorder. In this model, first proposed by as a prostaglandin deficiency , the focus is on alterations of the physicochemical properties of the biomembrane of the cell. In its simplest form, the theory posits an aberrant composition of constituents of the cell membrane leading to a multitude of biological changes. The focus has been on phospholipids and polyunsaturated fatty acids (PUFAs), especially deficiency of omega-3 fatty acids . Clinical evidence for the usefulness of supplementation with omega-3 fatty acids has been mixed, several small studies showing excellent improvement, one double-blind trial being negative

TROPHIC FACTORS• The prototypical course of schizophrenia can be characterized

as a time-limited progression of illness to a defect state . Possible targets include neurotrophic factors that regulate processes putatively disturbed in schizophrenia: neuronal and glial differentiation, migration, and proliferation. some aspect of schizophrenia can be understood as a fault in synaptic pruning. A clearer understanding of the cellular pathways that maintain synaptic connectivity and control apoptosis (such as the role of bcl-2) and their role in schizophrenia. These pathways might provide important targets for disease-modifying treatments or at a minimum lead to drugs that do not add additional neurotoxicity. White matter abnormalities can be seen with diffusion MRI and recently abnormal expression of genes involved in myelination has been found in schizophrenia brain. It is of interest that clozapine significantly affects lipid metabolism;

TROPHIC FACTORS• Current drug targets are generally focused on extracelluar

receptors. As a result,pharmacological approaches remain limited to influencing neuronal systems through manipulating the initiation phase rather than the adaptation phase. Very likely, future understanding of pathophysiology will shift the focus from receptors to downstream (post receptor) signal transduction pathways located inside the cell and more specifically influencing gene expression. A case in point is the phosphoprotein DARPP-32 which integrates dopaminergic and other signaling pathways. Its central position in dopamine signaling makes it an attractive target for disorders of dopamine regulation. and the more speculative goal of producing drugs that influence brain development, perhaps by enhancing myelination-stimulating neurotrophic factors, or protecting the brain against putative neurotoxic factors such as free radicals from impaired or overwhelmed oxidative stress defenses

Novel Neurotransmitter Mechanisms Other Than Serotonin and Dopamine

• Sigma antagonists• Originally categorized as one type of opiate receptor, they are

now associated with the actions of the psychotomimetic agent phencyclidine (PCP) and the activity of the N-methyl-d-aspartate (NMDA) subtype of glutamate receptors. Theoretically, a sigma antagonist could block any PCP-like actions occurring in schizophrenia. Although early testing of the sigma antagonist BMY-14,802 in schizophrenia was not impressive, other antagonists with greater selectivity, especially SR31742A, have been developed and have entered testing. A combined sigma/5HTlA agonist/5HT reup-take inhibitor, OPC14523, is being tested in depression.

Cannabinoid antagonists.

• An antagonist to cannabinoid 1 (CB1) receptors, SR141716A, reduces the activity of mesolimbic dopamine neurons in animal models, suggesting possible antipsychotic actions in schizophrenia and leading to testing in schizophrenic patients.

Neurotensin antagonists.

• Neurotensin is a peptide neurotransmitter, which is colocalized with dopamine in the mesolimbic dopamine pathway, but is much lower in concentration in the nigrostriatal and mesocortical dopaminergic pathways. A non-peptide antagonist SR-142948 is in clinical testing in schizophrenia as a theoretical agent that could reduce positive symptoms without producing EPS by exploiting differential actions on the mesolimbic rather than nigrostriatal dopamine system.

Cholecystokinin

• Cholecystokinin (CCK) is also colocalized with dopaminergic neurons and has two receptor subtypes, CCK-A being predominantly outside of and CCK-B within the central nervous system. Studies of CCK agonists and antagonists to date have not given clear clues as to their potential for therapeutic actions in schizophrenia.

Substance P and the neurokinins.

• The substance P and neurokinin family of peptide neurotransmitters was extensively discussed in Chapter 5 (see Figs. 5—69 through5—73). Antagonists to all three neurokinin receptors (i.e., NK-1, NK-2, and NK-3) are now in clinical testing for a variety of indications, predominantly depression. Several are being tested in schizophrenia as well.

Future Combination Chemotherapies for Schizophrenia

• psychopharmacological treatments for psychotic disorders in the future will use multiple drugs simultaneously to attain therapeutic synergy. Combination chemotherapy uses the approach of adding together several independent therapeutic mechanisms. When successful, this results in a total therapeutic response that is greater than the sum of its parts. This approach often has the favorable consequence of simultaneously diminishing total side effects, since adverse experiences of multiple drugs are mediated by different pharmacological mechanisms and therefore should not be additive. Clinical trials with multiple therapeutic agents working by several mechanisms can be quite difficult to undertake, but it may be an approach that should be applied to complex neurodegenerative disorders with multiple underlying disease mechanisms, such as schizophrenia. Thus, schizophrenia treatments of the future will combine an atypical antipsychotic for positive and negative symptoms and for mood, cognition, and hostility, without causing EPS, tardive dyskinesia, or hyperprolactinemia, with some sort of booster treatment to attain even better relief of negative symptoms and cognitive symptoms. Possibly an additional neuroprotective agent will be helpful if stopping future psychotic episodes alone is not sufficient to arrest the downhill course of illness. In the long run, some sort of molecular-based therapy to prevent genetically programmed disease progression or to reverse the consequences of aberrant neurodevelopment may also form part of the portfolio of treatments for schizophrenia.