Psychopharmacological Enhancement of Neurocognition in Schizophrenia

Snapshot and Updates From the 14th International Congress on Schizophrenia Research

Persons with schizophrenia experience neurocognitive deficits-difficulties with mem­ory, attention, quick thinking, problem solving/reasoning, and other thinking skills (Table 1)-that decrease their quality of life and functional status and increase their risk of relapse.¹ Antipsychotics do little to reduce these impairments; therefore, there has been considerable effort to develop treatments that would specifically improve cognition in persons with schizophrenia.^2,3 These treatments include rehabilitative interventions that capitalize on neuroplasticity and behavioral principles such as cognitive remediation.⁴

This article summarizes efforts to develop neurocognitive enhancement drugs administered individually or as an adjunct to other antipsychotics and cognitive remediation. It includes clinical updates from the 14th International Congress on Schizophrenia Research (ICOSR) regarding the efficacy of psychopharmacological neurocognitive enhancement.

The answer to the question “are there medications that can improve cognition in schizophrenia patients?” is an elusive one. Our growing knowledge of the neurobiology and neurochemistry of neurotransmission in schizophrenia has led to the development of medications that capitalize on different strategies or mechanisms (Table 2), yet treating neurocognitive impairments with medications remains a challenge.⁵ Only a few medications have been developed and tested to target each mechanism, and the results of studies are often mixed. In studies that showed significant improvements in neurocognition with a neurocognitive enhancer, the benefits were often small compared with placebo.⁵ The following is an update on the development and testing of neurocognitive-enhancing drugs.

Dopaminergic
Dihydrexidine (DAR-0100) is a dopamine D1 receptor agonist that seems practical for neurocognitive enhancement, since it is able to cross the blood-brain barrier to act directly on receptors. Its possible benefits have not, however, been studied extensively in schizophrenia. In the only published study to date, no evidence of neurocognitive benefits was found in 20 stable outpatients given either a 20-mg subcutaneous dose of DAR-0100 or placebo.⁶ At the ICOSR, Siever and colleagues7 reported on pilot data obtained from 14 patients with schizotypal personality disorder who received 15 mg of DAR-0100A or placebo. They found that DAR-0100A produced improvements in working memory and context processing. It may be that the less severe neurocognitive impairments in schizotypal personality disorder are more responsive to DAR-0100 treatment than are impairments in schizophrenia.

Cholinergic
Only one study, by Buchanan and colleagues,8 found that galantamine improved working memory and verbal learning; otherwise, drugs targeting cholinergic activity have failed to improve neurocognition in schizophrenia. Freedman and colleagues9 had previously reported a failed trial of 3-(2,4-dimethoxy) benzylidene anabaseine (DMXB-A), an α7 nicotinic receptor partial agonist. At the ICOSR, they reported on another study comparing its neurocognitive benefits as an add-on (150 mg bid) with risperidone or olanzapine.10 Before DMXB-A was added, patients taking olanzapine had better neurocognitive functioning than patients taking risperidone. After adjunctive DMXB-A was given to both groups, patients taking risperidone had greater improvement in neurocognitive function than patients taking olanzapine; average scores in both groups were close to the general population average.

Glutamatergic
In several clinical trials, researchers attended to a group of amino acids that promote glutamate activity by activating NMDA receptors (glycine, D-cycloserine, and d-serine), but results have been disappointing to date.⁵ Goff and colleagues¹¹ reported on the results of 2 clinical trials that examined the benefit of preventing, rather than promoting, glutamate release. They studied la­motrigine (100 to 400 mg/d), an anticonvulsant that blocks sodium channels and inhibits the spontaneous release of glutamate. They found that in their second sample of 212 patients, lamotrigine was associated with significant improvements in neurocognitive functioning.

At the ICOSR, a few presentations reported on the results of trials that evaluated the benefits of NMDA receptor agonists as adjuncts to cognitive remediation training. In 32 stable outpatients, Goff and colleagues¹² pro­vided cognitive remediation training 3 to 5 times weekly for 8 weeks plus once-weekly d-cycloserine (50 mg/d) or cognitive remediation training plus placebo. Both study groups demonstrated improvements in the learning of an auditory discrimination task, but only the cognitive remediation plus placebo group had improvements on overall neurocognition.

During the same session, D’Souza and colleagues¹³ reported on the results of their d-serine (30 mg/kg) enhancement of a 12-week cognitive remediation program (5 h/wk). They found no added benefit for the combination of cognitive remediation plus d-serine, although tolerable, over cognitive remediation plus placebo.

GABAergic
Some compounds, such as MK-0777, have been developed to influence γ-aminobutyric acid (GABA) activ­ity, but these have also failed to demonstrate neurocognitive benefits in large clinical trials.⁵ Recently, Geffen and colleagues¹⁴ showed that BL-1020, an antipsychotic enhanced with GABA agonist activity, improved neurocognition in schizophrenia patients; however, its benefits were not significantly greater than those of risperidone. In one study, Menzies and colleagues¹⁵ found that flumazenil, a GABAA antagonist improved working memory relative to placebo; relative to lorazepam, a GABAA agonist actually worsened working memory performance. However, the study sample was small (N = 11) and would benefit from replication.

Oxytocin
There has been recent interest in the role of the aptly named “bonding hormone” in schizophrenia-particularly its low expression levels and effect on negative symptoms and social-cognitive deficits.¹⁶ Social cognition, an important predictor of functioning in schizophrenia, refers to the processing of information about others and social situations, and it encompasses emotional and social reasoning. Studies have shown that adjunctive oxytocin improved clinical symptoms and aspects of social cognition in schizophrenia patients.¹⁷

At the ICOSR, Woolley and colleagues¹⁸ reported on a small study in which they gave intranasal oxytocin or placebo to 22 men with schizophrenia. They found that oxytocin improved the ability of these men to correctly judge others’ thoughts and understand the subtleties in language (eg, sarcasm, white lies).

In a well-attended session, Mar­der¹⁹ reported on the results of several studies from his group that evaluated the benefits of oxytocin. They found that a single 40-IU dose of oxytocin was not only tolerable but also improved patients’ ability to detect sarcasm and white lies in language. In another study, they found that as an adjunct to social cognition training, oxytocin improved higher-level social-cognitive skills, such as empathic accuracy, more than adjunctive placebo did.²⁰ All patients who received social cognition training demonstrated improvements in social cognition, but adjunctive oxytocin facilitated the gaining of empathic accuracy.

Conclusions
It does not appear that medications effectively treat neurocognitive impairments in schizophrenia, whereas adjunctive oxytocin appears to be beneficial for treating social-cognitive deficits in schizophrenia. While presentations at the 14th ICOSR showed promise for oxytocin, they did not raise enthusiasm for any neurocognition-enhancing drugs. Harvey and Bowie⁵ identified factors that may account for the limited efficacy of psychopharmacological agents for enhancing neurocognition (Table 3). Moreover, several aspects of pharmacological enhancement remain unexplored (Table 4).

Clearly, the neurobiological basis of neurocognitive deficits in schizophrenia is quite complex and not limited to a single target, but to several interconnected signaling systems. It may be that effective psychopharmacological enhancement would not only target activity at multiple receptor sites but also promote the synthesis and growth of new neurons. This may be accomplished through the development of dual-action agents or through strategic enhancement with polypharmacy. Polypharmacological enhancement may be impractical, however, because of the increased risk of adverse effects that may render a combined regimen of antipsychotics and multiple neurocognitive enhancers intolerable.

Disclosures:

Dr Ahmed is Assistant Professor and Research Psychologist in the department of psychiatry and health behavior at Georgia Regents University in Augusta. He reports no conflicts of interest concerning the subject matter of this article.

Dr Brian Miller, Psychiatric Times Section Editor for Schizophrenia, invited and reviewed this article.

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