Molecular targets for treating cognitive dysfunction in schizophrenia

Cognitive impairment is a core feature of schizophrenia as deficits are present in the majority of patients, frequently precede the onset of other positive symptoms, persist even with successful treatment of positive symptoms, and account for a significant portion of functional impairment in schizophrenia. While the atypical antipsychotics have produced incremental improvements in the cognitive function of patients with schizophrenia, overall treatment remains inadequate. In recent years, there has been an increased interest in developing novel strategies for treating the cognitive deficits in schizophrenia, focusing on ameliorating impairments in working memory, attention, and social cognition. Here we review various molecular targets that are actively being explored for potential drug discovery efforts in schizophrenia and cognition. These molecular targets include dopamine receptors in the prefrontal cortex, nicotinic and muscarinic acetylcholine receptors, the glutamatergic excitatory synapse, various serotonin receptors, and the gamma-aminobutyric acid (GABA) system.     

Novel mitochondrial targets for neuroprotection

Mitochondrial dysfunction contributes to the pathophysiology of acute neurologic disorders and neurodegenerative diseases. Bioenergetic failure is the primary cause of acute neuronal necrosis, and involves excitotoxicity-associated mitochondrial Ca(2+) overload, resulting in opening of the inner membrane permeability transition pore and inhibition of oxidative phosphorylation. Mitochondrial energy metabolism is also very sensitive to inhibition by reactive O(2) and nitrogen species, which modify many mitochondrial proteins, lipids, and DNA/RNA, thus impairing energy transduction and exacerbating free radical production. Oxidative stress and Ca(2+)-activated calpain protease activities also promote apoptosis and other forms of programmed cell death, primarily through modification of proteins and lipids present at the outer membrane, causing release of proapoptotic mitochondrial proteins, which initiate caspase-dependent and caspase-independent forms of cell death. This review focuses on three classifications of mitochondrial targets for neuroprotection. The first is mitochondrial quality control, maintained by the dynamic processes of mitochondrial fission and fusion and autophagy of abnormal mitochondria. The second includes targets amenable to ischemic preconditioning, e.g., electron transport chain components, ion channels, uncoupling proteins, and mitochondrial biogenesis. The third includes mitochondrial proteins and other molecules that defend against oxidative stress. Each class of targets exhibits excellent potential for translation to clinical neuroprotection.     

Novel targets for antidepressant therapies

Most depressed patients fail to achieve remission despite adequate antidepressant monotherapy, and a substantial minority show minimal improvement despite optimal and aggressive therapy. However, major advances have taken place in elucidating the neurobiology of depression, and several novel targets for antidepressant therapy have emerged. Three primary approaches are currently being taken: 1) optimizing the pharmacologic modulation of monoaminergic neurotransmission, 2) developing medications that target neurotransmitter systems other than the monoamines, and 3) directly modulating neuronal activity via focal brain stimulation. We review novel therapeutic targets for developing improved antidepressant therapies, including triple monoamine reuptake inhibitors, atypical antipsychotic augmentation, dopamine receptor agonists, corticotropin-releasing factor-1 receptor antagonists, glucocorticoid receptor antagonists, substance P receptor antagonists, N-methyl-d-aspartate receptor antagonists, nemifitide, omega-3 fatty acids, and melatonin receptor agonists. Developments in therapeutic focal brain stimulation include vagus nerve stimulation, transcranial magnetic stimulation, magnetic seizure therapy, transcranial direct current stimulation, and deep brain stimulation.     

Glutamatergic dysfunction--newer targets for anti-obsessional drugs

Despite widespread use and validation of their efficacy, about 40-60% of obsessive compulsive disorder (OCD) sufferers do not respond to appropriate courses of treatment with serotonin reuptake inhibitors (SRI) and even with the combination of pharmacotherapy and cognitive behaviour therapy a substantial number of patients remain dramatically symptomatic. Recently, there has been increasing interest in investigating glutamatergic dysfunction in OCD. Multiple lines of evidence point toward glutamatergic dysfunction being related to the pathophysiology of OCD, with glutamate modulating drugs being an alternative pharmacological strategy for treating OCD. In this article we focus in detail on the rationale for targeting glutamatergic agents as well as review the recent important patents for compounds that have emerged from these studies.     

Developing drugs for cognitive impairment in schizophrenia

There are strong data suggesting that improvement in the cognitive impairment associated with schizophrenia will contribute to enhanced functional outcomes for patients with this illness. Measurement and Treatment Research to Improve Cognition in Schizophrenia was established to provide a pathway for developing and registering potential cognitive-enhancing agents for this condition by addressing issues related to the content of the cognitive assessment battery and the clinical design features to be used in registration studies. This article examines key challenges related to the actual clinical development of cognitive-enhancing agents. These challenges include improving the probability of technical success and attrition rates of candidate molecules, establishing better animal models of human cognition, and developing biomarkers to decrease development costs and increase the speed of the clinical discovery process. Biomarkers are important for molecular target validation, dose selection, surrogate end points, and population segmentation. Examples of approaches for the development of agents for cognitive impairment associated with schizophrenia are discussed. It is concluded that close collaboration among academia, the National Institutes of Health, regulatory bodies, and industry will be important to advance the goal of developing drugs for this important condition.     

Novel therapeutic targets

Neurological Sciences - The need for novel therapeutic strategies for the treatment of migraine and other primary headaches is well recognised. Although the underlying mechanism(s) and the...     

Cognitive deficits as treatment targets in schizophrenia

Cognitive impairment has emerged as an important new target in schizophrenia therapeutics in light of evidence that cognitive deficits are critically related to the functional of disability that is characteristic of the illness. Evidence is briefly reviewed supporting the idea that the cognitive impairment in schizophrenia is an attractive target for therapeutic intervention including: (1) there is a characteristic pattern of cognitive deficits that occur with very high frequency; (2) the deficits are relatively stable over time; and (3) cognitive deficits are relatively independent of the symptomatic manifestations of the illness. Thus, cognitive impairment appears to be a well-defined, reliable and distinct dimension of the illness.     

Ghrelin receptors as targets for novel motility drugs

Constipation arises from a multitude of causes, including aging, spinal cord injury (SCI), and dietary issues. The heterogeneity of inciting factors has made the treatment of constipation particularly challenging. Agonists of ghrelin receptors have beneficial effects on delayed gastric emptying, but less is known about their ability to improve colorectal motility. Recent publications indicate that the activation of the ghrelin receptors in the spinal cord can alleviate constipation due to dietary causes, Parkinsonism, and SCI in rodents. Ghrelin‐responsive neurons in the intermediolateral cell column of the lumbosacral spinal cord can activate enteric microcircuits that coordinate propulsive colorectal contractions, leading to defecation. Learning more about the properties of neurons in the spinal defecation center and the roles of ghrelin receptors in the defecation reflex will accelerate the development of improved treatments of constipation.     

Catecholaminergic drugs in chronic schizophrenia.

The effect of dopaminergic-related and stimulatory drugs have been studied in chronic hebephrenic schizophrenics untreated with neuroleptic drugs. 6 patients received therapy of 2 g L-dopa + 200 mg carbodopa per day orally for 30 days, then placebo for 30 days. Following that 3 of the same patients received therapy of 2 g L-dopa + 200 mg carbodopa + 300 mg imipramine orally for 30 days, then placebo for 30 days. Following that the same 3 patients received 1 mg apomorphine s.c. for 15 days, then placebo for 15 days, then 1 mg apomorphine s.c. + 2 g L-dopa + 200 mg carbodopa per os daily for 15 days, then placebo for 15 days. The patients were examined psychologically by the Wittenborn Rating Scale, the Weigl Object-Sorting Test, and tests for verbal learning and verbal association, before and after each therapeutic trial. Levels of FSH, LH, testosterone and GH were assayed radioimmunologically before, in the middle of and after each course of therapy. 2 patients showed improvement in the affective-behavioural symptomatology during therapy, while the other 4, who had a more severe degree of mental deterioration and destruction, were unchanged. FSH and LH levels, very low under basal conditions, did not change under therapy. Testosterone was very low before therapy and increased in only 1 subject. Normal basal GH levels increased during therapy in some of the patients, but not constantly. The results obtained are discussed in relation to the catecholamine hypotheses of schizophrenia.     

GABAA receptors as targets for novel anxiolytic drugs.

Anxiety disorders are highly prevalent and disabling disorders which are commonly treated with pharmacotherapy and/or psychotherapy. While benzodiazepines are of great value for the treatment of acute anxiety states, their long-term use is hampered by their well-known side effect profile. Meanwhile, antidepressants represent first line treatment options for anxiety disorders. However, their slow onset of action is a disadvantage for their use in these disorders. Therefore, there is need for novel anxiolytics with a rapid onset of action and a favourable side effect profile. Currently, there is a renaissance of gamma-aminobutyric acid type A (GABAA) receptors as targets for the development of novel anxiolytic drugs. While compounds structurally related to GABA, e.g., pregabalin, have already entered large scale clinical development, GABA transporter inhibitors, subtype specific benzodiazepines and GABAA receptor modulating neuroactive steroids are promising new candidates. However, their clinical efficacy has still to be shown in clinical trials.     

Neurobiological background for the development of new drugs in schizophrenia

Psychopharmacology of schizophrenia has remained static for many years because the mechanisms explored have been basically monoaminergics, primarily focused toward the modification of dopaminergic function and, later on, serotonergic. In fact, most of the antipsychotics introduced in clinical practice in the last years have been antagonists or selective agonists of these receptors (D(2)/5-HT(2)). The exploration of other receptor pathways, and in particular those additionally involved in the action of the paradigmatic "atypical" antipsychotic clozapine (ie, cholinergic and noradrenergic), has not been very significant. Besides, research in the antipsychotics field has developed also by exploring pathways that are beyond the spectrum of clozapine. Among the most promising mechanisms are those based on the glutamatergic hypothesis of schizophrenia (agonists at the glycine-binding modulatory site of the N-methyl-D-aspartate receptor, glycine transporter inhibitors, modulators of the AMPA [α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid] receptor and selective agonists of the metabotropic receptor Glu(2)). Other less classic pathways are also under study and have led to some agents that are found in very early stages of development such as those acting on sigma receptors, cholecystokinin antagonists, neurotensin agonists, neurokinin receptor antagonists, GABAergic (+-aminobutyric acid [GABA]) enhancers, and cannabinoid(gamma-aminobutiric) receptor modulators.     

Use of antidepressant drugs in schizophrenia.

This review surveys the therapeutic efficacy of tricyclic antidepressants and monoamine oxidase inhibitors in schizophrenic patients. In general, the use of these drugs alone was found not to be warranted in schizophrenia, except perhaps in the so-called pseudoneurotic subgroup. In most cases, combinations of antidepressants and phenothiazines were not more beneficial than phenothiazines alone. In particular, the conditions of agitated patients and patients with histories of social deviance dating back to childhood were often made worse by the addition of an antidepressant. However, when the patients who demonstrated symptoms of clinical depression other than anergia were isolated from several of these studies, it was found that they constituted a subgroup that was often benefited by use of these combinations. Favorable and unfavorable clinical response patterns are discussed, and recommendations for future research are outlined.     

Psychotropic drugs and depressive syndrome in schizophrenia

Lifelong records of schizophrenic illnesses were examined in order to compare the occurrence and characteristics of depressive syndrome in the pre-phenothiazine era and with neuroleptic treatments. It was found that a depressive syndrome similar to endogenous depressive psychosis develops spontaneously and independently of neuroleptic medication. The relationship of this endogenous syndrome to the postpsychotic depression of other origin is discussed.