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Evidence-Based Reviews


Do cholinesterase inhibitors enhance cognition in schizophrenia?

Disorder’s heterogeneity may help explain why the answer is unclear.

Vol. 7, No. 3 / March 2008
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Some schizophrenia patients have shown significant improvements in positive and negative symptoms when my colleagues and I added acetylcholinesterase inhibitors (AChEIs) to their anti-psychotic regimens. We cannot rule out these benefits as placebo effects, but nevertheless they have been sustained over time. When patients appear to have benefited from AChEIs but stopped them, the benefits rapidly disappeared. Then, when these patients restarted the medications, the benefits recurred.

Unfortunately, recent well-controlled clinical studies have not supported these anecdotal findings or the results of approximately 20 preliminary trials. Thus, this article explains:

  • why we don’t recommend using off-label AChEIs as a “first choice” augmentation strategy in schizophrenia patients at this time
  • under what circumstances the adjunctive use of these agents might be reasonable.

Why Alzheimer’s medications?

Schizophrenia and Alzheimer’s disease (AD) have dramatically different onset, symptoms, course, and pathophysiology. As reviewed below, schizophrenia patients are no more likely to develop AD than the general population, and AChEIs—even when effective—have a short-term, limited benefit in AD.

So why are psychiatrists trying AD medications in patients with schizophrenia? The answer has to do with the intriguing effects of cholinergic agents on cognition.

Toward cognitive enhancement

Schizophrenia’s cognitive impairments may occur at a very early age, often before other overt symptoms,1 then may worsen—sometimes to dementia levels—when obvious psychotic symptoms emerge.2

Positive symptoms (hallucinations, delusions, thought disorder, etc.) and—to a lesser extent—negative symptoms (anhedonia, asociality, blunted affect, etc.) often improve when patients are treated with antipsychotics. Antipsychotics do not significantly improve cognitive symptoms (attention, reaction time, working memory, verbal fluency, etc.), however, and cognitive symptoms are the strongest predictors of poor functional outcomes in our patients.

Heterogeneous disorder. In 2000, Cummings3 summarized evidence from case re-ports and small studies that AChEIs were useful in treating neuropsychiatric conditions other than AD (Table 1). Cholinergic agents, Cummings noted, “affect many aspects of cognition, which suggests that the primary effect may be on an attentional or executive system with a secondary, pan-intellectual modulating influence on memory, language, and visuospatial skills.”4

In schizophrenia, different patients have different types of cognitive impairment.5 Thus, broad-based cognitive enhancers such as AChEIs may be necessary for general use in this illness.

Acetyltransferase activity. Schizophrenia patients—even those meeting criteria for dementia—do not usually have typical AD neuropathology, and the incidence of AD is no different in elderly patients with or without comorbid schizophrenia.6 At autopsy, schizophrenia patients and normal controls have similar brain cortical choline acetyltransferase levels.

Nevertheless, persons with AD and those with schizophrenia show a similar, statistically significant negative correlation between premorbid Clinical Dementia Rating scale scores and brain cortical choline acetyltransferase activity (r=– 0.36, P <0.0003 vs r=– 0.29, P <0.005, respectively).6 Furthermore, studies have found cholinergic neurotransmission alterations in schizophrenia patients, including:

  • a deficit in regulation of the low-affinity alpha-7 nicotinic receptor in those with impaired sensory gating7
  • altered high-affinity nicotinic receptor binding8
  • decreased hippocampal muscarinic receptor binding compared with matched normal controls9
  • reduced density of cholinergic inter-neurons in the ventral striatum.10

These findings—plus the presumably “nonspecific” benefits of AChEIs in many illnesses3—suggest that some patients with schizophrenia may have deficits in nicotinic and/or muscarinic cholinergic neurophysiology, which might be amenable to pharmacologic supplementation.

Table 1

Cholinesterase inhibitors have shown benefit in many neuropsychiatric conditions*

Alcoholism with Wernicke’s encephalopathy

Attention-deficit/hyperactivity disorder

Autism

Bipolar disorder

Creutzfeldt-Jakob disease

Dementia pugilistica

Dementia with Lewy bodies

Olivopontocerebellar atrophy

Parkinson’s disease with dementia

Parkinsonism dementia complex of Guam

Pick’s disease

Progressive supranuclear palsy

Schizophrenia

Sleep disorders

Subacute sclerosing panencephalitis

Traumatic brain injury

Vascular dementia

* Data from case reports and small studies. Cholinesterase inhibitors are FDA-approved only for Alzheimer’s dementia.

Source: Reference 3

AChEI augmentation

Mixed results. A number of investigators—including myself—have published data indicating that adding AChEIs—most often donepezil, but also rivastigmine or galantamine—to antipsychotic regimens may improve some schizophrenia patients’ symptoms and general functioning. These benefits were modest, however, when they were seen in these relatively small case reports and studies (Box).

Box

Early studies: Modest benefit from AChEIs in schizophrenia

Approximately 20 published studies have reported clinically significant benefits (positive symptom, negative symptom, and/or cognitive improvement) when schizophrenia patients received cholinesterase inhibitors with their antipsychotic regimens. These include case reports, case series, and double-blind, placebo-controlled, crossover or parallel-design studies, most with relatively small numbers of subjects.a-o

Recent studies, however, have failed to show a clinically or statistically significant benefit from cholinesterase inhibitor augmentation in schizophrenia (Table 2). Some included larger sample sizes than earlier investigations and a placebo-active drug parallel design.

fMRI findings. A few crossover design studies of schizophrenia patients taking antipsychotics included functional magnetic resonance imaging (fMRI) at baseline and after cholinesterase inhibitor and placebo augmentation. Of interest, the basal “abnormal” pattern of the baseline fMR image became more “normal” when subjects were treated with donepezil.

Source: Click here to view references

Other studies of AChEI augmentation of typical or atypical antipsychotics have been:

  • equivocal, reporting benefits in some but not all patients (with no clear statistical or clinical conclusions) or in schizophrenia patients with comorbid dementia11-14
  • decisively negative, showing no benefits, particularly in comparatively larger, randomized, placebo-controlled trials (Table 2).15-19

Meta-analysis power. In an attempt to understand these wide-ranging results, Chouinard et al20 performed an elegant meta-analysis of oral AChEI augmentation therapies for cognitive enhancement in schizophrenia. This review emphasized the available studies’ complexity, small number and sample sizes, and small benefit effect sizes.

The authors concluded that—based on preliminary data—adjunctive AChEIs seemed to have “some beneficial effects” on attention and memory for schizophrenia patients.

The last word? Within weeks, however, results of a large multicenter trial by Keefe et al21 showed that donepezil augmentation was no more effective than placebo in improving cognition in patients with schizophrenia or schizoaffective disorder. In this 38-center, randomized, double-blind, placebo-controlled, parallel design study, 250 patients with mild to moderate cognitive impairment received adjunctive donepezil—5 mg/d for 6 weeks, then 10 mg/d for 6 weeks—or placebo for 12 weeks.

Both the treatment and placebo groups experienced statistically and clinically significant benefits from baseline in measures of cognition, positive symptoms, and negative symptoms. For all measures, placebo augmentation was equal to or superior to donepezil augmentation.

Table 2

Controlled trials: No benefit from AChEIs in schizophrenia

Study design

Subjects

Drug (dosage)

Results

Friedman et al (2002),15 double-blind, placebo-controlled

36 patients with schizophrenia

Donepezil, 5 or 10 mg/d for 12 weeks

Neither dose produced significant improvement in any cognitive measure

Tugal et al (2004),16 double-blind, placebo- controlled, crossover

12 patients with stable schizophrenia

Donepezil, 5 mg/d for 6 weeks, with crossover to placebo for 6 weeks

Treatment effect was not significant in any cognitive measure

Freudenreich et al (2005),17 double-blind, placebo-controlled

36 stable outpatients with schizophrenia

Donepezil, ≤10 mg/d for 8 weeks

No improvement in cognition or psychopathology measures

Sharma et al (2006),18 randomized, double-blind, placebo-controlled

21 patients with stable schizophrenia

Rivastigmine, 12 mg/d for 24 weeks

No significant improvement in any cognitive measure

Fagerlund et al (2007),19 double-blind, placebo-controlled

21 patients enrolled, 11 completed

Donepezil, 5 or 10 mg/d for 4 months added to ziprasidone

No differences in changes on PANSS scores or a global cognitive score

Keefe et al (2007),21 randomized, double-blind, placebo-controlled

250 stable outpatients with schizophrenia or schizoaffective disorder

Donepezil, 5 mg for 6 weeks then 10 mg for 6 weeks

Donepezil was well-tolerated but did not improve cognition any more than placebo

PANSS: Positive and Negative Syndrome Scale

Analyzing trial results

The large, well-designed clinical trial by Keefe et al21 suggests conclusively that donepezil augmentation is not more effective than placebo in most stable schizophrenia or schizoaffective disorder patients with mild to moderate cognitive impairment.

Even so, it is arguably difficult to “prove a negative.” For example:

  • Different dosages might have been more effective.
  • Longer treatment (>3 months) might have been necessary for donepezil to “surpass” the large placebo effect.
  • Other AChEIs—such as galantamine, which stimulates nicotinic receptors—might be more effective than donepezil, which is predominantly muscarinic.

‘Subgroup’ hypothesis. Finally, if schizophrenia’s pathophysiology is extremely heterogeneous, AChEI augmentation might benefit only the small subgroup of patients with decreased cholinergic activity. Most other patients—without decreased cholinergic activity—would not benefit or might even worsen. In support of the “subgroup” hypothesis, Miller22 has reported that many augmentation agents have efficacy in schizophrenia—but only in a minority of patients.

If this hypothesis is true, clinicians would need to differentiate patients before giving them trials of AChEIs or other augmentation therapies. Genetic testing might identify different pathophysiologies among patients, but these technologies are not yet clinically available.

Recommendations

Clinical experience, case reports, and small case series indicate that occasional patients may benefit from AChEI augmentation. On the other hand, the only large, multi-center, placebo-controlled, parallel-design study found no difference between donepezil and placebo augmentation of atypical antipsychotics.21

Thus this review of available evidence does not support the routine use of AChEI augmentation of typical or atypical antipsychotics as a viable psychopharmacologic strategy. Until more supportive evidence has been reported, this reviewer cannot recommend AChEIs as a “first line” augmentation strategy. Furthermore, because these medications do not have an FDA-approved indication in schizophrenia and are expensive, a cost-benefit appraisal also would not support their routine use.

Nevertheless, AChEIs are relatively safe and occasionally have been dramatically effective in a small subgroup of schizophrenia patients when used as augmentation. They may represent a reasonable approach:

  • when other adjuncts have failed
  • as a supplement to other augmentation strategies, such as cognitive-behavioral therapy or family therapy.

Related resources

  • Mohamed S, Paulsen JS, O’Leary D, et al. Generalized cognitive deficits in schizophrenia. Arch Gen Psychiatry 1999;56:749-54.
  • Risch SC, Horner MD, McGurk S, et al. Double-blind donepezil-placebo crossover augmentation study of atypical antipsychotics in chronic, stable schizophrenia: a pilot study. Schizophr Res 2007;93:131-5.

Drug brand names

  • Donepezil • Aricept
  • Rivastigmine • Exelon
  • Galantamine • Reminyl, Razadyne
  • Ziprasidone • Geodon

Disclosure

Dr. Risch receives research support from the National Institute of Mental Health, Abbott Laboratories, GlaxoSmithKline, Bristol-Myers Squibb, and Forest Pharmaceuticals. He is a consultant to and speaker for AstraZeneca and Pfizer Inc.

References

1. Hans SL, Marcus J, Nuechterlein KH, et al. Neurobehavioral deficits at adolescence in children at risk for schizophrenia. The Jerusalem Infant Development Study. Arch Gen Psychiatry 1999;56:741-8.

2. Heaton R, Paulsen JS, McAdams LA, et al. Neuropsychological deficits in schizophrenia: relationship to age, chronicity and dementia. Arch Gen Psychiatry 1994;51(6):469-76.

3. Cummings JL. Cholinesterase inhibitors: a new class of psychotropic compounds. Am J Psychiatry 2000;157(1):4-15.

4. Lawrence AD, Sahakian BJ. Alzheimer disease, attention, and the cholinergic system. Alzheimer Dis Assoc Disord 1995;9(suppl 2):43-9.

5. Green MF, Kern RS, Broff DL, et al. Neurocognitive deficits and functional outcome in schizophrenia: are we measuring the “right stuff”? Schizophr Bull 2000;26:119-36.

6. Powchick P, Davidson M, Haroutunian V, et al. Postmortem studies in schizophrenia. Schizophr Bull 1998;24(3):325-41.

7. Breese CR, Lee MJ, Adams CE, et al. Abnormal regulation of high affinity nicotinic receptors in subjects with schizophrenia. Neuropsychopharmacol 2000;23(4):351-64.

8. Crook JM, Tomaskovic-Crook E, Copolov DL, Dean B. Decreased muscarinic receptor binding in subjects with schizophrenia: a study of the human hippocampal formation. Biol Psychiatry 2000;48(5):381-8.

9. Holt DJ, Bachus SE, Hyde TM, et al. Reduced density of cholinergic interneurons in the ventral striatum in schizophrenia: an in situ hybridization study. Biol Psychiatry 2005;58:408-16.

10. MacEwan GW, Ehmann TS, Khanbhai I, Wrixon C. Donepezil in schizophrenia—is it helpful? An experimental design case study. Acta Psychiatr Scand 2001;104(6):469-72.

11. Stryjer R, Strous RD, Bar F, et al. Beneficial effect of donepezil augmentation for the management of comorbid schizophrenia and dementia. Clin Neuropharmacol 2003;26:12-7.

12. Aasen I, Kumari V, Sharma T. Effects of rivastigmine on sustained attention in schizophrenia: an fMRI study. J Clin Psychopharmacol 2005;25:311-7.

13. Arnold DS, Rosse RB, Dickinson D, et al. Adjuvant therapeutic effects of galantamine on apathy in a schizophrenia patient. J Clin Psychiatry 2004;65:1723-4.

14. Friedman JI, Adler DN, Howanitz E, et al. A double blind placebo controlled trial of donepezil adjunctive treatment to risperidone for the cognitive impairment of schizophrenia. Biol Psychiatry 2002;51:349-57.

15. Tugal O, Yazici KM, Anil Y, Gögüs A. A double-blind placebo controlled, cross-over trial of adjunctive donepezil for cognitive impairment in schizophrenia. Int J Neuropsychopharmacol 2004;7:117-23.

16. Freudenreich O, Herz L, Deckersbach T, et al. Added donepezil for stable schizophrenia: a double-blind, placebo-controlled trial. Psychopharmacology. (Berl) 2005;181:358-63.

17. Sharma T, Reed C, Aasen I, Kumari V. Cognitive effects of adjunctive 24-weeks rivastigmine treatment to antipsychotics in schizophrenia: a randomized, placebo-controlled, double-blind investigation. Schizophr Res 2006;85:73-83.

18. Fagerlund B, Soholm B, Fink-Jensen A, et al. Effects of donepezil adjunctive treatment ziprasidone on cognitive deficits in schizophrenia: a double-blind, placebo-controlled study. Clin Neuropharmacol 2007;30:3-12.

19. Chouinard S, Sepehry A, Amir A, et al. Oral cholinesterase inhibitor add-on therapy for cognitive enhancement in schizophrenia: a quantitative systematic review, part I. Clin Neuropharmacol 2007;30:169-82.

20. Keefe RS, Malhotra AK, Meltzer HY, et al. Efficacy and safety of donepezil in patients with schizophrenia or schizoaffective disorder: significant placebo/practice effects in a 12-week, randomized, double-blind, placebo-controlled trial. Neuropharmacol 2007;July 11 [Epub ahead of print].

21. Maelicke A, Albuquerque EX. Allosteric modulation of nicotinic acetylcholine receptors as a treatment strategy for Alzheimer’s disease. Eur J Pharmacol 2000;393:165-70.

22. Miller AL. Combination treatments for schizophrenia. CNS. Spectr 2004;9(9):19-23.

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