Cognitive impairment in schizophrenia

A number of meta-analyses have examined the extent of cognitive impairment in people with schizophrenia (Reference Heinrichs and ZakzanisHeinrichs 1998; Reference Aleman, Hijiman and De HaanAleman 1999; Reference Bokat and GoldbergBokat 2003). Large effect sizes (between 1 and 1.5), representing robust evidence of impairment, have been reported across a multitude of cognitive domains, including current IQ, category fluency, verbal memory, abstract thinking, language, sustained attention and response inhibition. Symbol coding tasks yielded some of the most robust evidence, with very large effect sizes. However, Reference Hyde, Nawroz and GoldbergHyde et al (1994) performed a cross-sectional study to assess cognitive performance in schizophrenia across a wide age range. A comparison of scores on cognitive measures recorded for five age-derived cohorts showed no evidence of accelerated decline on the Mini-Mental State Examination (MMSE), the Dementia Rating Scale, list learning, semantic fluency or perseverative errors on the Wisconsin Card Sorting Test.

Do people with schizophrenia develop dementia?

In his Lehrbuch der Psychiatrie of 1893, Kraepelin used the term ‘dementia praecox’ (premature dementia) for schizophrenia because of its onset in early life and the characteristic development of ‘mental enfeeblement’. He emphasised the progressive deterioration of cognition but noted that memory was spared. He distinguished this condition from paraphrenia in which cognitive impairment did not occur.

Over a century later, there is uncertainty about the course of cognitive function with ageing in schizophrenia. Early studies of the progression of dementia over the lifespan in individuals with schizophrenia have shown inconsistent results, although they were limited by a lack of standardised diagnostic criteria and specific evaluation techniques.

In a study of long-term in-patients with schizophrenia who had survived into old age, Reference Harvey, Parella and WhiteHarvey et al (1999a) followed up a group for 30 months using the Clinical Dementia Rating (CDR). Over this period, 30% of the patients deteriorated, from a baseline of minimal or mild cognitive and functional impairment to impairments severe enough to warrant a secondary diagnosis of dementia.

Although many studies suggest a model of schizophrenia as a progressive dementing illness, others have supported the view that cognitive impairment in schizophrenia fits the model of a static encephalopathy (Reference Goldberg, Hyde and KleinmanGoldberg 1993; Reference Hyde, Nawroz and GoldbergHyde 1994).

Evidence from international studies

Neuropathology and post-mortem evidence

Reference K⊘rner, Lopez and LauritzenKørner et al ’s (2009) finding of an increased risk of developing dementia in their schizophrenia cohort might be explained by confounding diagnostic factors. For example, Alzheimer’s disease or vascular dementia might have presented atypically or have been undiagnosed by clinicians reluctant to make a diagnosis in the context of schizophrenia. People with schizophrenia often have unhealthy lifestyles and inadequate physical healthcare, both of which are vascular risk factors for Alzheimer’s disease and vascular dementia. However, post-mortem neuropathological studies do not support this hypothesis.

Reference Purohit, Davidson and PerlPurohit et al (1993) studied the presence of senile plaques and neurofibrillary tangles in the post-mortem brains of a small number of elderly patients with schizophrenia and cognitive impairment, comparing them with the brains of age-matched patients with Alzheimer’s disease. It was noted that none of the brains from the group with schizophrenia showed a sufficient degree of senile plaques and neurofibrillary tangles to make the diagnosis of Alzheimer’s disease. Despite advanced age and cognitive impairment, however, the density of senile plaques was sparse in the majority of samples from the schizophrenia group. The authors concluded that cognitive impairment cannot be explained by increased vulnerability to Alzheimer’s disease. Other (mostly small-sample) studies using immunohistochemistry have failed to show any increased incidence of Alzheimer’s disease pathology in people dying with schizophrenia and cognitive impairment.

A subsequent study by Reference Purohit, Perl and PowchikPurohit et al (1998) examined 100 consecutive autopsy brains from patients with schizophrenia, and compared them with the brains from normal controls and from patients with non-schizophrenic psychoses. In previous cognitive assessments, 72% of the patients with schizophrenia had shown moderate to severe cognitive impairment. However, postmortem examination revealed that only 9% met neuropathological criteria for Alzheimer’s disease. This study demonstrates that, although severe cognitive impairment is commonly observed in schizophrenia, it is only occasionally due to comorbid Alzheimer’s disease.

The findings from post-mortem studies are summarised in Box 2.

If the pathology is not that of Alzheimer’s disease, what is its neuropathological basis? Most dementia in schizophrenia is not characterised by classic, histologically identifiable neuropathology and most is probably not the result of an identifiable dementing illness.

Neurochemistry

A number of neurochemical abnormalities have been identified in cognitively impaired patients with schizophrenia. Although some of these are shared with Alzheimer’s disease, many are not. For example, cortical somatostatin and serotonin levels are similar in schizophrenia and Alzheimer’s disease, whereas cortical corticotrophin-regulating hormone and acetylcholine levels are dissimilar. Cognitively impaired patients with schizophrenia show cortical deficits of vaso-active intestinal peptide and neuropeptide Y, and increased senile plaque concentrations in the cingulate and temporal cortex (Reference Powchik, Davidson and HaroutunianPowchik 1998). In addition, there is some evidence of a reduction in concentrations of serotonin and noradrenaline in cognitive impairment. It has also been shown that people with a diagnosis of schizophrenia and dementia without Alzheimer’s disease do not show significantly elevated levels of amyloid β-peptide, which is increased in the post-mortem brains of Alzheimer’s disease patients (Reference Religa, Laudon and StyczynskaReliga 2003). This last study suggested that antipsychotics may actually protect against the development of Alzheimer’s disease pathology.

Diagnosis

The assessment of people with schizophrenia presenting with features of dementia can be difficult for several reasons. First of all, it can be clearly demonstrated that a substantial percentage of people with schizophrenia develop cognitive dysfunction early in their illness, so a retrospective history may not give a clear-cut picture of recent changes. However, a detailed history from both the patient and an informant with close personal knowledge of them over time may reveal a pattern of increasing cognitive decline. The history and assessment should include orientation, memory, personality changes and activities of daily living. Effective cognitive testing is essential on presentation, as is information about the patient’s previous level of functioning.

Diagnosis at this stage would be made easier if cognitive testing early in the lifespan of patients with schizophrenia were routine. There is a growing consensus that cognitive deficits characterising schizophrenia should be incorporated into the major diagnostic systems, including the DSM and ICD (Reference Bora, Yucel and PantelisBora 2010). Such a development would prompt clinicians to assess a patient’s cognitive profile early in the course of schizophrenia. This, in turn, might stimulate new treatment methods and promote better management of cognitive impairment and dementia in schizophrenia. The emphasis should be on recognising whether cognitive deficits have been stable over time or there has been a significant decline from a premorbid level of cognitive function, particularly in later life. The question of whether longitudinal assessments of cognitive function would have predictive value needs further research.

The correct diagnosis of dementia in people with schizophrenia (Box 3) is largely dependent on the expertise and skill of the clinician carrying out the assessment. However, the measurement of cognitive function required to inform the diagnosis raises a vexing question: What tools, measures and approaches should the clinician use to assess cognition? To complicate matters further, cognitive decline, a core feature of both schizophrenia and dementia, is found to some extent in normal ageing. Moreover, all these evaluations require the patient’s cooperation.

Brain imaging and diagnosis

Technological advances have led to a greater use of structural and functional brain imaging to assist with the diagnosis of dementia in people with evidence of cognitive decline. Additional information obtained from these investigations helps clinicians to make an accurate diagnosis and formulate a treatment plan. In clinical practice, structural magnetic resonance imaging (MRI) and computed tomography (CT) scanning are widely used, and radiologists interpret results on the basis of visual readings.

Structural imaging is often carried out to identify potentially treatable causes of dementia, such as normal pressure hydrocephalus or space-occupying lesions, or to clarify the diagnosis by detecting cerebral infarctions (strokes) or patterns of atrophy. In cognitively impaired patients without a definite clinical diagnosis, MRI may be helpful in reaching a diagnosis. Without MRI investigation the clinical diagnosis of vascular dementia may be unreliable. Image analysis programs that quantify regional volumes in MRI (and CT) have shown that measures of medial temporal or hippocampal atrophy can distinguish people with Alzheimer’s disease from controls. Several studies have shown ventricular enlargement, cerebral infarction or white matter ischaemic change using CT or MRI scans. However, these findings are non-specific in both Alzheimer’s disease and vascular dementia.

The results of CT investigation of brain structure in schizophrenia have been variable. The most consistent finding has been lateral ventricular enlargement, although the cause of this remains unclear. Computed tomography and MRI could give an insight into biological abnormalities in patients with schizophrenia and dementing illness, but studies are limited in this group. Reference Förstl, Dalgalarrondo and Riecher-RösslerFörstl et al (1994) compared CT scans of patients with late-onset paranoid psychosis with those of patients with Alzheimer’s disease and of elderly controls with dementia. They found that the ventricles and anterior and Sylvian fissures of the psychosis group were larger than in the controls but smaller than in those with Alzheimer’s dementia. However, these non-specific findings alone do not help the clinician to distinguish dementia in schizophrenia from dementia due to Alzheimer’s disease or vascular disease or, indeed, to distinguish people with dementia from those without.

Functional imaging technologies such as single-photon emission computed tomography (SPECT), positron emission tomography(PET)and functional MRI (fMRI) also provide information about brain structure, but their spatial resolution is lower than with CT or structural MRI. The added value of functional scanning is the information provided on cerebral blood flow or glucose metabolism, even when structural deficits are not present. This can help the physician in the diagnosis and differential diagnosis of dementia (Reference Silverman, Small and ChangSilverman 2001). Patients with Alzheimer’s disease typically show parietal, temporal, posterior cingulate and frontal deficits, whereas those with frontotemporal dementia show frontal and temporal deficits (Reference Silverman, Small and ChangSilverman 2001). Dementia with Lewy bodies has a pattern similar to that of Alzheimer’s disease, but with additional occipital deficits. However, there are no studies of dementia associated with schizophrenia.

As the clinical use of neuroimaging techniques expands, investigators are exploring novel applications of existing techniques and developing others that measure various biological processes relevant to neurodegeneration. Combining neuroimaging studies with other procedures that provide data on genetic risk and biomarker measures from other tissues (e.g. blood serum, cerebrospinal fluid) might increase diagnostic sensitivity and specificity, as well as the predictive value of the information.

For a summary of this section, see Box 5.

Management

A major issue in the management of dementia in schizophrenia is which services are best suited to provide care for patients (Box 6). Health policy in the UK requires the early identification and management of dementia and the active inclusion of people with dementia in the decision-making process (Department of Health 2001). However, there are only a few high-quality evaluations of models of care in dementia (National Collaborating Centre for Mental Health 2011), and even these show a particular lack of data from user and carer perspectives.

The Royal College of Psychiatrists (2006) has made recommendations for service provision for younger people with dementia. A study comparing old age psychiatrists and neurologists found that younger patients may be underinvestigated if solely managed by old age psychiatrists, and may not receive adequate follow-up if managed by neurologists (Reference Cordery, Harvey and FrostCordery 2002). On the whole, old age psychiatrists may be best equipped to manage these patients, provided that they work in close collaboration with the appropriate specialists, for example neurologists.

Memory clinics have become established as a response to an increased demand for dementia assessment and care. Such clinics do not adhere to a single type of service model or delivery, but they have features in common: they are usually for people with mild to moderate dementia; a thorough assessment is conducted; diagnoses are made; and pharmacological treatment may be initiated and monitored. Although it is possible to evaluate cases of dementia in schizophrenia in these clinics, an already overburdened service may not be able to meet all the demands of patients with such complex needs. Where dementia services are provided across the age range, they should construct themselves to be acceptable and to meet the needs of people with early-onset dementia and their carers as well as those with dementia in old age (Reference Willis, Chan and MurrayWillis 2009). Services that are designed to treat people with dementia need to develop strategies to care for those with subjective memory impairment but no objective deficits.

People with comorbid schizophrenia and dementia may need specific management of their psychosis. It may be argued that general adult mental health services are better equipped to deal with schizophrenia, whereas old age mental health services have expertise in dementia. General adult and old age mental health services may need to cooperate to provide a service that meets all the needs of these patients. Both services should be able to advise people on healthy living (Box 7).

Drug treatment

Prognosis of dementia in schizophrenia

Dementia shortens the lifespan. At any given age, people who have dementia are two to four times more likely to die than those who do not have the disease (Reference Dewey and SazDewey 2001; Reference Guehne, Angermeyer and Riedel-HellerGuehne 2006). The median survival time of people with dementia has been investigated in cohort studies and case series in various settings, and it ranges from 3 to 9 years (Reference Dewey and SazDewey 2001; Reference Xie, Brayne and MatthewsXie 2008). However, longitudinal comparisons of the course of cognitive and functional decline have been very few in the subpopulation with dementia in schizophrenia. Reference MayerMayer (1921) found that many of Kraepelin’s patients with paraphrenic psychoses showed unequivocal signs of dementia later in the course of illness. Reference HoldenHolden (1987) observed that people with late paraphrenia had significantly worse outcomes when they developed dementia.

As mentioned earlier, Reference Goldberg, Hyde and KleinmanGoldberg et al (1993) stated that schizophrenia can be regarded as a static encephalopathy. Some studies suggest that the progressive cognitive decline experienced by people with poor-outcome (long-term institutionalised) schizophrenia is not a linear process across the lifespan, and the rate of decline may accelerate after the age of 65 (Reference Friedman, Harvey and ColemanFriedman 2001).

Again, more studies are needed, on both the survival rates and prognosis of people with schizophrenia once they develop dementia (Box 8).

The future

The lack of evidence-based knowledge in the area of dementia in schizophrenia is highly evident. In particular, it is not yet clear whether there is an excess of dementia in schizophrenia, be it of early or late onset. A sustained cognitive impairment suggesting a diagnosis of dementia does not always occur, but Kraepelin’s concept of dementia praecox appears to be right at least some of the time. It is debatable whether we under- or over-diagnose dementia in this group of patients. We need naturalistic studies to investigate this. Research needs to concentrate on accurately diagnosing dementia in schizophrenia using the best neuropsychological methods available, in combination with brain imaging and post-mortem examination. As we learn more about the genetics of schizophrenia and the subtypes of dementia, a complicated but better understood picture will emerge.

Another underresearched area is how best to manage dementia in schizophrenia. Healthy lifestyles are clearly desirable, but as yet there is little hard evidence of any benefit for people with schizophrenia or with dementia, let alone with both. Acetylcholinesterase inhibitors look promising as an augmentative treatment and there are many more antidementia medications under development.

As populations across the world age, so does the population of people with schizophrenia. Age is the biggest risk factor for dementia, and since over 20% of the general population of over-80-year-olds have dementia (Department of Health 2001), the proportion is likely to be higher among those with schizophrenia. We need to push the needs of this group up the health agenda and develop more and better services to meet them.

MCQs

Select the single best option for each question stem

1. 1 As regards schizophrenia:

   1. a cognitive impairment is a feature of schizophrenia

   2. b cognitive impairment is a criterion used to diagnose schizophrenia in DSM-IV and ICD-10

   3. c cognitive impairment always progresses in schizophrenia

   4. d Alzheimer’s disease invariably develops in older people with schizophrenia

   5. e dementia in schizophrenia is accepted as a separate nosological entity.

2. 2 Of the following, the least useful scale for the diagnosis of dementia with schizophrenia is:

   1. a the MMSE

   2. b the CERAD neuropsychological battery

   3. c the MATRICS battery

   4. d the ACE-R

   5. e the ADAS-L Cog.

3. 3 Radiological signs specific in diagnosing dementia in schizophrenia include:

   1. a hippocampal atrophy

   2. b ventricular enlargement

   3. c white matter lesions

   4. d temporal lobe atrophy

   5. e none of the above.

4. 4 Of the following, the least useful in improving cognition in comorbid dementia and schizophrenia is thought to be:

   1. a first-generation antipsychotics

   2. b second-generation antipsychotics

   3. c galantamine

   4. d rivastigmine

   5. e donepezil.

5. 5 As regards the diagnosis of dementia in schizophrenia:

   1. a cognitive impairment always means that dementia is present

   2. b the presence of dementia in schizophrenia usually means that post-mortem examination will reveal Alzheimer’s disease pathology

   3. c functional imaging shows a clear diagnostic pattern

   4. d the diagnosis can be made only after a history of cognitive and functional decline has been identified

   5. e the diagnosis should only be made by an old age psychiatrist.

MCQ answers

1

a

2

a

3

e

4

a

5

d