Cognitive impairment is a core feature of schizophrenia, with more than 80% of patients showing significant impairments (Keefe & Fenton, 2007). The range of cognitive impairments in individuals with schizophrenia is broad, with the more robust and replicable deficits typically found in the domains of processing speed, episodic memory, working memory and executive function. These impairments have been shown to be associated with various impaired functional outcomes and thus development of new therapies to enhance cognition has become one of the most pressing challenges. Cognitive deficits persits throughout the course of the illness and as such, negatively affect daily functioning, work outcomes and treatment adherence. While anti-pscyhotic medications can control psychotic symptoms for the majority of patients, such improvements do not automatically transfer into the functional outcome, such as community functioning. Additionally, anti-psychotic drugs that are currently the main form of treatment in schizophrenia demonstrate only a modest positive effect on cognition.
Despite a large number of compelling rationales and significant body of preclinical data, there are no dramatic or consistent results that any one medication has the power to increase cognitive skills to the level of normal functioning. While a wide range of cholinergic, dopaminergic, glutamatergic and cannabinoid compounds have been developed, the Food and Drug Administration (FDA) has not yet approved any of the drug development programmes specifically aimed at treating cognitive impairments in schizophrenia.
Pharmacological approach: Potential Cognitive-Enhancing Drugs in Schizophrenia
- Antipsychotic Drugs (APDs)
While numerous studies have demonstrated the dramatic efficacy of APDs in suppressing psychotic symptoms and preventing their recurrence, they have also revealed their inability to alleviate the negative and cognitive symptoms of the illness. There are, however, some studies that suggest that some of the newer atypical antipsychotics e.g. aripiprazole, clozapine, quetiapine, olanzapine, risperidone and ziprasidone, may provide minimal benefits in certain specific areas of cognition.
- Donepezil, Rivastigmine, Galantamine
Researchers sometimes focus on drugs that have proved effective in other cognitively impaired conditions, such as in dementia. Several drugs approved for dementia stimulate acetylcholine by blocking its breakdown, which has been shown to improve cognition and slow cognitive decline. Donepezil belongs to this type. The results in schizophrenia field, however, are not very encouraging, with only a few studies showing somewhat minimal memory improvement.
Rivastagime has also been investigated but only in smaller-scale studies. No significant findings have been reported to date.
Evidence of cognitive benefit with galantamine has been mixed so far. The overall trend indicates that at lower doses galantamine exerts a positive effect on cognition but at higher doses it is consistently associated with negative results. The most effective dosage is yet to be established.
- Nicotine and nicotinic receptors
It is now widely accepted that nicotinic receptor abnormalities are present in schizophrenia. The vast majority of studies found some positive effects, improvements were frequently recorded in working memory and attentional/executive control functions and in episodic memory. However, nicotine did not improve every measure examined in each study and the magnitude of the effects was not large. Additionally, nicotine as a therapeutic agent may be limited by tachyphylaxis.
Modafinil is a wakefulness-promoting agent, shown to be effective in enhancing cognition in sleep-deprived and healthy individuals, as well as in some psychiatric disorders. While having effect on many neurotransmitter systems, modafinil has an uncertain mechanism of action. Results at this stage appears to be inconclusive. Benefits demonstrated by early studies were not replicated by larger-scale studies.
NB: Non-pharmacological applications will be reviewed in a future post
Keefe, R. S. E., & Fenton, W. S. (2007). How should DSM-V criteria for schizophrenia include cognitive impairment? Schizophrenia bulletin, 33(4), 912-20. doi:10.1093/schbul/sbm046