The Effect of Antipsychotics on Cognition in Schizophrenia

Despite the proven efficacy of antipsychotics it was estimated that 30 to 60% of patients with schizophrenia ultimately become unresponsive or only partially responsive to treatment with conventional antipsychotics (Meltzer, 1992). Neuroleptics were associated with the reduction of psychotic symptoms of schizophrenia, but they did not demonstrate any significant impact on cognitive features of the disease (Sweeney et al., 1991).

Cognitive dysfunction a core deficit

The dichotomic positive-negative symptoms concept of schizophrenia was implicated in the 1980s (Crow, 1980; Andreasen, 1982) and the emphasis was on a reduction of negative symptoms by pharmacological and non-pharmacological methods. But the 1990s identified cognitive dysfunction as a core deficit in schizophrenia and important outcome measure. Cognitive impairment always was intrinsically linked to schizophrenia. Since Kraepelin’s first description of dementia praecox, cognitive impairment has been intrinsically linked to schizophrenia.

"Overincluding" thinking

After Bleuler, the schizophrenia psychological model of specifically disordered cognition process based mostly on the concept of associative psychology has dominated for decades. Outstanding Russian neuropsychologist Luria considered that researchers must find the main neuropsychological factor, which determines the clinical symptoms of mental patients (Luria, 1966). Cameron characterized the thinking of schizophrenics as "overincluding".

For example, the patient, solving a problem, uses a redundant number of categories or redundant information (Cameron, 1944). Later, Russian neuropsychologists proposed that the core cognitive lesion in schizophrenia is a lack of selectivity of actual knowledge from available experience due to a decrease of the motivational component of mental activity and the need of communication (Polyakov, 1973).

Less specific lesions

Recently, less specific cognitive lesions were confirmed in the schizophrenic population. As a group, schizophrenic patients have neurocognitive deficits in perception, attention, information processing speed, motor skills, memory, and executive function. These neurocognitive deficits have been found to occur before the onset of the positive symptoms and antipsychotics treatment (Gold & Harvey, 1993).

Independent of positive symptoms

Cognitive dysfunction is recognized now as a primary deficit that is independent of positive symptoms and persists after their resolution (Sharma & Harvey, 2000). Social outcome is somewhat correlated with cognitive impairments. Improvements of neurocognitive deficits have been reported to be better predictors of functioning than improvements in psychotic symptomatology (Green, 1996). Several studies suggested strong association between cognitive deficits and poor social and/or occupational outcomes (Green, 1996, Brekke et al., 1997).

Conventional antispsychotics

Conventional antipsychotics, which primarily block D2 dopamine receptors, may demonstrate no effect (Berman et al., 1986) or minimal beneficial effect on cognitive functioning (Serper et al., 1994) or can even further impair cognitive functioning (Sweeney et al., 1991). Also, traditional antipsychotics cause extrapyramidal symptoms (EPS), which significantly decrease speed on cognitive tasks involving motor output and readiness to respond.

In summary, according to numerous studies (reviewed in Cassens et al., 1990, King, 1990, Sharma, 1999), there is evidence that the effect of conventional antipsychotics on schizophrenia cognitive impairment is minor except occasional improvement in attention (King, 1990). In addition, treatment of EPS with anticholinergic drugs can impair mnestic functioning.

Anticholinergic activity shared

Moreover, some classical neuroleptics such as chlorpromazine and thioridazine also share anticholinergic activity. Acute treatment with typical neuroleptics can result in a deterioration in some aspects of attention and motor behavior (Cassens et al., 1990, King, 1990, Bilder et al., 1992). However, these negative effects decrease with chronic treatment. Performance on tests of executive function such as the Wisconsin Card Sorting Test (Heaton, 1981) remains unaltered by traditional neuroleptics. Typical neuroleptic drugs lack the ability to improve the various domains of cognitive function impaired in schizophrenia.

More favorable side-effect profile

New generation antipsychotics such as clozapine, olanzapine, risperidone and quetiapine are characterized by a more favorable side-effect profile than conventional antipsychotics. In particular they produce fewer extrapyramidal symptoms than typical neuroleptic drugs and have more potent antagonism of 5HT2a receptors relative to D2 receptors.

Newer antipsychotic drugs showed promise in ameliorating neurocognitive deficits in schizophrenia. A growing body of evidence suggests that patients taking new generation antipsychotics perform better on some neurocognitive tests than patients taking standard neuroleptics (Gallhofer , 1996; Rossi et al., 1997, Purdon, 1998). New generation antipsychotics are supposed to improve neurocognitive deficits especially in first-episode schizophrenia (Good et al., 2002).

Improvement of attention and verbal fluency

Some studies provide strong evidence that clozapine improves attention and verbal fluency and moderate evidence that clozapine improves some types of executive function. However, results of the effects of clozapine on working memory and secondary verbal and spatial memory were inconclusive (Meltzer, McGurk, 1999). Lee et al. (1999) suggested that clozapine is superior to typical neuroleptics in improving specific types of cognitive function in recent onset, neuroleptic-responsive schizophrenia.

Risperidone and olanzapine

Direct beneficial effects of risperidone were provided by demonstrated improvement on verbal working memory (Green et al., 1997), Additionally, risperidone appeared to improve executive functioning (Rossi et al., 1997), verbal learning and memory (Kern et al., 1999). Risperidone has relatively consistent positive effects on working memory, executive functioning, and attention, whereas improvement in verbal learning and memory was inconsistent.

Our own study showed that schizophrenic patients receiving risperidone had significantly better executive functions from 6 months of therapy than haloperidol group, and this effect did not depend on episode number (Kabanov et al., 2001, Soulimov et al., 2001, Kabanov, Mosolov, 2002).

Olanzapine improves verbal learning and memory, verbal fluency, and executive function, but not attention, working memory, or visual learning and memory (Meltzer, McGurk, 1999).

Cognitive deficit

Cognitive deficit in schizophrenics exists before prominent positive and negative symptoms. Symptomatology, motivation, institutionalization etc. cannot explain these deficits, which are of considerable importance for both the testing of theoretical models of schizophrenia and the determination of patients' functional outcome (Mortimer, 1997). Second generation antipsychotic agents may be effective in amelioration of some cognitive deficits associated with schizophrenia (Rossi et al., 1997, Meltzer& McGurk, 1999). Beneficial effects of new generation antipsychotics on cognition have implications for social functioning.

Design faults

Unfortunately, many of the studies suffered from design faults such as a lack of placebo or control group, inadequate washout period, nonrandom assignment to treatment, use of polypharmacy, mixed study populations, and a lack of long-term follow-up studies.

The major improvement in cognition was observed through three months and progressively went on through the year. Therefore, assessment of drug effects on cognitive function requires a long evaluation period.

Several methodological issues may contribute to these discrepancies, namely

1. the impact of extrapyramidal symptoms on neuropsychologic performance
2. less than optimal dosage
3. duration of treatment before assessment of cognitive function
4. failure to determine whether the progress in neuropsychologic performance was primarily caused by drug effects or secondary effects related to improvement in psychopathology
5. patient selection
6. neuropsychologic test selection
7. study design

(Sharma, Mockler, 1998).

It is suggested that the development of drugs for schizophrenia should focus on improving the key cognitive deficits in schizophrenia: executive function, verbal fluency, working memory, verbal and visual learning and memory, and attention.

Main cognitive benefit

The main cognitive benefit of the new generation antipsychotics is probably due to their low liability for causing EPS. Direct action on a wide range of receptors might be responsible for improving not only negative symptoms but also cognition. The proposed mechanism of this beneficial effect on cognition is an antagonism of 5-HT2a receptors, which in turn activates dopaminergic neurons projecting the prefrontal cortex.

The effect of the drug might also have an indirect association through the normalization of attentional processing (King, 1994). When selecting neuropsychological tests to evaluate cognitive function, there is a risk that small but significant effects could be missed because of heterogeneity in the study groups.

Future direction

The future direction of studies investigating the clinical efficacy of newer antipsychotics should consider cognition as an important outcome measure. Further longitudinal studies are needed to determine the effect of new generation antipsychotics on cognitive deficits in schizophrenia and its interaction with positive and negative symptoms.

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