Lately, you’ve probably seen a lot of articles in the journals (not to mention in the journal ads) about targeting cognition in schizophrenia. Latuda (lurasidone), the latest FDA approved antipsychotic, is being talked up to have “pro-cognitive” effects—whatever that means. (See accompanying article by Dr. Sewell for a review of lurasidone.) In what ways, if any, are cognitive problem a distinct feature of schizophrenia? And how can we use this information to guide treatment?

To understand this, it is helpful to review the DSM-IV criteria for the diagnosis of schizophrenia. There are five cardinal symptoms: delusions, hallucinations, disorganized speech, disorganized behavior, and negative symptoms. In some sense, each of these symptoms reflects a cognitive problem, but this is not what researchers mean when they describe “cognitive deficits” in schizophrenia.

A delusion is an inaccurate thought, and a hallucination is an inaccurate perception. Neither are deficits. Disorganized speech usually refers to patterns like looseness of associations and circumstantiality—again, not really a cognitive deficit, but rather a thought pattern gone haywire. Disorganized behavior is the inability to perform basic tasks of living, such as properly dressing oneself, cooking, shopping, and so forth.

Here we begin to shade into the realm of cognitive deficits. If you have a poor memory, for example, you might get lost in the middle of a task. Finally, negative symptoms sound even more like cognitive deficits: lack of emotion, poor social functioning, and apathy.

Researchers have created a special taxonomy of cognitive domains that often are impaired in schizophrenic patients (Neuchterlein et al, Schizophr Res 2004;72(1):29–39). A glance at these seven cognitive domains in table 3 shows how essential these abilities are for everyday functioning. 

Potentially Impaired Cognitive Domains in Schizophrenia
Many patients with schizophrenia have deficits in all modalities, although the specific pattern may vary from person to person. Some of these deficiencies may even be seen in childhood and precede the onset of schizophrenia (Reichenberg A et al, Am J Psychiatry 2010;167(2):160–169). Furthermore, deficiencies in these domains have had, in most but not all studies to date, a greater impact on everyday function (eg, work performance or the ability to live independently) than even the presence of positive or negative symptoms (Keefe RSE and Fenton WS, Schizophr Bul 2007;33(4):912–920).

Treating Cognitive Deficits
Do standard antipsychotics, whether typical or atypical, improve cognitive deficits in schizophrenia? Unfortunately, there is little evidence that they do. The CATIE trial, which compared five antipsychotics (one conventional and four atypical) in 817 patients, included a composite cognitive score as one of its endpoints. All patients showed a modest improvement in this cognition measure after two months, but no single antipsychotic outperformed any other (Keefe RSE, World Psych 2008;7:22–28). Moreover, the extent of improvement may have been due to “practice effect,” or simply the patients’ increasing familiarity with the tests over time, and the fact that the majority (60%) of patients had been on antipsychotic medication prior to the study.

In the EUFEST trial of 286 patients with first-episode schizophrenia, most of whom had never taken antipsychotics, all antipsychotics studied (haloperidol (Haldol) and four atypical) gave rise to modest cognitive improvement on a five-test neuropsych battery (effect sizes 0.35 to 0.50). However, all antipsychotics performed equally, and data analysis showed that most of the cognitive benefit was attributable to overall symptom improvement rather than a specific pro-cognitive effect (Davidson et al, Am J Psychiatry 2009;166(4):675–682s).

Some of us are tempted to prescribe “neuroenhancing” drugs (Hyman SE, Neuron 2011;69(4):595–598) to treat cognitive deficits in their patients with schizophrenia. Although they sometimes seem to work in individual cases, results of larger clinical trials have not been encouraging. Off-label use of agents as diverse as donepezil (Aricept), memantine (Namenda), methylphenidate (Ritalin), atomoxetine (Strattera), and modafinil (Provigil) have been tested in randomized controlled trials but have shown little to no benefit relative to placebo (reviewed in Harvey PD, Neuropsychol Rev 2009;19(3):324–335).There have been case reports of psychostimulants worsening psychosis—so you should be especially cautious if you try one of them.

An obstacle to FDA approval of pro-cognitive drugs in schizophrenia is the fact that the FDA generally does not approve drugs for symptoms of an illness, especially when those symptoms may be common to other diagnoses.

To overcome this methodological obstacle to scientific progress, in 2002 the NIMH—in conjunction with the FDA, six academic centers and several pharmaceutical companies—developed the MATRICS (Measurement And Treatment Research to Improve Cognition in Schizophrenia) initiative (www.matrics. ucla.edu).

The MATRICS group developed a battery of neuropsychological tests (www.matricsinc.org/MCCB.htm) and additional “functionally meaningful measures” for testing new compounds (Green MF et al, Am J Psychiatry 2011;168(4):400–407). The goal of MATRICS is to create a pathway for drug development, both for novel antipsychotics with pro-cognitive effects and for adjunctive agents (see Green MF, Ann Rev Clin Psychol 2007;3:159–180).

A wide range of new neuropharmacological agents for improving cognitive function are waiting in the wings. These include alpha-7 nicotinic receptor agonists (spurred by the observation that nicotine seems to sharpen cognition in schizophrenic patients), D1 receptor agonists, AMPA glutamatergic receptor agonists, alpha-2 adrenergic receptor agonists, and others (reviewed in Barch DM, Curr Topics Behav Neurosci 2010;4:43–96). Thus far, these compounds have been tested in animal models of learning and memory—and unfortunately, at this point they don’t seem to be any more effective than standard antipsychotics (Barak S and Weiner I, Pharm Biochem Behav 2011;online ahead of print).

The good news is that the MATRICS program has helped researchers test various non-drug interventions as adjuncts to medications. For example, in one study 55 schizophrenic patients were randomized to either 50 hours of computerized verbal processing training or playing computer games. Those in the treatment group showed significant gains in global cognition and verbal learning and memory (for example, see Fisher M et al, Am J Psychiatry 2009;166(7):805–811). By clearly defining outcome variables, MATRICS appears to be improving the quality of research.

So what are the take home points for the front line clinician? First, you should review the table of basic cognitive domains, and start evaluating them in your schizophrenic patients. While this may not affect the DSM diagnosis, it will encourage you to record your patients’ impairments more precisely. This, in turn, will help you to decide whether a particular treatment seems to be improving cognition.

Antipsychotics provide very modest improvement in cognitive function in schizophrenia, but there’s no reason to recommend one over any other. Neuroenhancers and newer experimental agents show no consistent benefit, but the broader use of the MATRICS tools may change this. As an adjunct to antipsychotic treatment, nonpharmacological interventions may be effective.