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.
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 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 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.
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
- the impact of extrapyramidal symptoms on neuropsychologic performance
- less than optimal dosage
- duration of treatment before assessment of cognitive function
- failure to determine whether the progress in neuropsychologic performance was primarily caused by drug effects or secondary effects related to improvement in psychopathology
- patient selection
- neuropsychologic test selection
- 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.
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.
1. Andreasen NC. Negative symptoms in schizophrenia. Definition and reliability. Arch Gen Psychiatry 1982;39:784 –788.
2. Berman KF, Zec RF, Weinberger DR. Psychologic dysfunction of dorsolateral prefrontal cortex in schizophrenia: II. Role of neuroleptic treatment, attention and mental effort. Arch Gen Psychiatry 1986;43:126-135.
3. Bilder RM, Turkel E, Lipschutz-Broch L et al. Antipsychotic medication effects on neuropsychological functions. Psychopharmacol Bull 1992;28:353-66.
4. Brekke JS, Raine A, Ansel M et al. Neuropsychological and psychophysiological correlates of psychosocial functioning in schizophrenia. Schizophr Bull 1997;23:19-28.
5. Cameron N. Experimental analysis of schizophrenic thinking. Language and thinking in schizophrenic. New York, 1944.
6. Cassens G, Inglis AK, Appelbaum PS, Gutheil TG. Neuroleptics: effects on neuropsychological function in chronic schizophrenic patients. Schizophr Bull 1990;16 (3):477-499.
7. Crow TJ. Positive and negative schizophrenic symptoms and the role of dopamine: Discussion 2. Br J Psychiatry 1980;137:383-386.
8. Gallhofer B, Bauer U, Lis S et al. Cognitive dysfunction in schizophrenia: comparison of treatment with atypical antipsychotic agents and conventional neuroleptic drugs. Eur Neuropsychopharmacology 1996;6:13-20.
9. Gold JM, Harvey PD. Cognitive deficits in schizophrenia. Psychiatr Clin North Am 1993;16:295-312.
10. Good KP, Kiss I, Buiteman C. et al. Improvement in cognitive functioning in patients with first-episode psychosis during treatment with quetiapine: an interim analysis. Br J Psychiatry 2002;181:45-49.
11. Green MF What are the functional concequences of neurocognitive deficits in schizophrenia? Am J Psychiat 1996;153:321-330.
12. Green MF, Marshall BD, Wirshing WC et al. Does risperidone improve verbal working memory in treatment-resistant schizophrenia? Am J Psychiatry 1997; 154:799-804.
13. Heaton RK. Wisconsin Card Sorting Test Manual. Odessa, FL: Psychological Assessment Resources, 1981.
14. Kabanov S.O., Mosolov S.N., Kalinin V.V. The effect of atypical and conventional antipsychotics on visual reconstructive memory in schizophrenia patient. The World Journal of Biol. Psychiat, 2001, vol.2, suppl.1, p.42.
15. Kabanov S.O., Mosolov S.N. Cognitive functioning under treatment with risperidone and haloperidol in acute phase of schizophrenia. Schizophrenia Research, 2002, vol. 53, N3, Suppl., 193-194.
16. Kern RS, Green MF, Marshall BD et al. Risperidone versus haloperidol on secondary memory: can newer medications aid learning? Schizophr Bull 1999;25: 223-232.
17. King DJ. The effect of neuroleptics on cognitive and psychomotor function. Br J Psychiatry 1990;157:799-811.
18. King DJ. Psychomotor impairment and cognitive disturbances induced by neuroleptics. Acta Psychiatr Scand 1994;38 (suppl):53-8.
19. Lee MA, Jayathilake K, Meltzer HY. A comparison of the effect of clozapine with typical neuroleptics on cognitive function in neuroleptic-responsive schizophrenia. Schizophr Research1999;37:1-11.
20. Luria AR. Higher cortical functions in man. (trans. Haigh B.) Basic Books, New York, 1966.
21. Meltzer HY. Treatment of the neuroleptic-nonresponsive schizophrenic patient. Schizophr Bull 1992;18:515-42.
22. Meltzer HY, McGurk SR. The effects of clozapine, risperidone, and olanzapine on cognitive function in schizophrenia. Schizophr Bull 1999;25:233-255.
23. Mortimer AM. Cognitive function in schizophrenia - do neuroleptics make a difference? Pharmacol Biochem Behav 1997;56:789-795.
24. Polyakov UF. Schizophrenia und Erkenntnistatigkeit. Hippokratus Verlag, Stuttgart, 1973, 179 p.
25. Purdon SE Neuropsychological change in early phase schizophrenia over twelve months of treatment with olanzapine, risperidone, or haloperidol. Schizophr Research 1998;29:152-153.
26. Rossi A, Mancini F, Stratta P et al. Risperidone, negative symptoms and cognitive deficit in schizophrenia: an open study. Acta Psychiatr Scand 1997;95:40-43.
27. Serper MR, Davidson M, Harvey PD. Attentional predictors of clinical change during neuroleptic treatment in schizophrenia. Schizophr Research 1994;13:65-71.
28. Sharma T. Cognitive effects of conventional and atypical antipsychotics in schizophrenia. Br J Psychiatry 1999;174(suppl. 38): 44-51.
29. Sharma T, Mockler D. The cognitive efficacy of atypical antipsychotics in schizophrenia. J Clin Psychopharmacol 1998;18(suppl 1):12-19.
30. Sharma T, Harvey PD. Cognitive enhancement as a treatment strategy in schizophrenia. In: Sharma T, Harvey PD (eds) Cognition in schizophrenia: impairment, importance, and treatment strategies. Oxford Press, 2000, pp 286-302.
31. Soulimov G.Y., Kalinin V.V., Kabanov S.O., Mosolov S.N. The influence of risperidone long-term treatment on performance of Trail Making Test in schizophrenic patients. VIIIth World Congress of Biol. Psychiat., 1-6 July 2001, Berlin – Berlin, 2001, p.81.
32. Sweeney JA, Keilp JG, Haas GL et al. Relationships between medication treatments and neuropsychological test performance in schizophrenia. Psychiatry Res 1991;37(3):297-308.
Published on CNSforum 24 May 2004