|Marco M Picchioni and Robin Murray (2008), Scholarpedia, 3(4):4132.||doi:10.4249/scholarpedia.4132||revision #90760 [link to/cite this article]|
Schizophrenia is a psychiatric disorder and falls within the scope of psychotic illnesses, meaning that the patient at some point develops symptoms that lead them to misinterpret reality. More specifically schizophrenia is characterised by the presence of certain symptoms and signs, in particular delusions and hallucinations, and thought disorganisation. The name schizophrenia derived from the early observation that the illness is typified by the disconnection or splitting of the psychic functions (Bleuler, 1911). Unfortunately, this has lead to the misconception that the illness is somehow characterised by a split personality, which is not the case.
How has the concept of schizophrenia evolved?
In the early 1800s many believed in a single psychotic illness "Einheitpsychose", though by the early 1850s two French psychiatrists Falret and Morel had distinguished "folie circulaire" or manic depressive psychosis from "demence precoce", a progressive disorder characterised by social withdrawl, self neglect and bizarre behaviour. Hecker employed the term "hebephrenia" to describe a very similar clinical concept to "demence precoce", while Kahlbaum proposed "catatonia" to describe a presentation of psychosis but dominated by episodes of abnormal movement and posture.
Emil Kraepelin united the concepts of "hebephrenia" and "catatonia" with "paranoia" into a single disorder "dementia praecox". Kraepelin too believed that this was a progressive disorder beginning in early adult life, which was characterised by delusions and hallucinations, disordered thought, loss of interest in the outside world and loss of emotional reactions.
Eugen Bleuler, a Swiss psychiatrist proposed in 1911 that there was not one illness "dementia praecox" but rather "a group of schizophrenias" and identified what he felt were the primary and secondary symptoms for this disorder. He suggested the primary symptoms were ambivalence, autism, (loss of interest in the outside world), affective blunting (loss of emotional responses) and altered associations (thought fragmentation). In contrast he felt the secondary symptoms, delusions and hallucinations while often present were not specific to schizophrenia.
Perhaps the most significant subsequent attempt to clarify the clinical definition of schizophrenia was proposed by Kurt Schneider in 1950. He regarded certain symptoms as particularly indicative of the disorder, such as particular types of auditory hallucinations and labelled these "first rank symptoms". The Schneiderian concept of schizophrenia has remained dominant into early 21st century diagnostic thinking though it is not without its weaknesses, in particular Schneider’s first rank symptoms are neither present in every patients with schizophrenia nor necessarily prove the presence of the disorder.
- Schneiders First Rank Symptoms of Schizophrenia.
- Thought block
- Thought deprivation
- Thought insertion
- Thought diffusion/broadcasting
- Thoughts being spoken aloud
Criticisms of the concept of schizophrenia
The very concept of schizophrenia has remained contentious, perhaps reaching its zenith with the anti-psychiatry movement of the 1960s. Psychiatrists such as Thomas Szasz and R.D. Laing viewed schizophrenia as a medical fallacy and more a handy sociological construct serving relatives and the public rather than the needs of the patient. Laing in particular emphasised the role of schizophrenia as a reaction to the demands of modern life and a process that of itself served a therapeutic purpose. Others have postulated that many of the negative features of the illness may in fact be a consequence of being labelled with such a stigmatising diagnosis rather than any inherent facet of the disorder itself.
Psychosis as a dimension and the schizophrenia spectrum
The theoretical issue of whether the symptoms of schizophrenia are absolutely different from the experiences of the normal population has never been fully settled. While schizophrenia is usually conceptualised as a dramatic departure from normal health, attenuated versions of many of the same symptoms can occur in healthy people or the unaffected relatives of patients, and are not necessarily associated with illness (Hanssen et al, 2005). This has lead to the conclusion that schizophrenia reflects a quantitative (degree) rather than qualitative (absolute) deviation from normality, rather like hypertension or diabetes mellitus. Similarly the clinical boundaries of schizophrenia remain indistinct blending at one extreme with bipolar disorder and at the other with schizotypal (personality) disorder.
Symptoms and signs: How does schizophrenia present?
One of the commonest symptoms in schizophrenia is hearing sounds or voices, auditory hallucinations. A hallucination is defined as a perception without a stimulus causing it. Hallucinations can occur in any sensory modality though in schizophrenia they are usually auditory. Very often the voices are experienced as personally critical or abusive or instruct the patient what to do. “What did you do that for?”, “He's stupid”, “She can’t do anything right.” (Nayani & David, 1996) Many patients employ a variety of coping strategies, both behavioural and cognitive that can have a significant impact on the presence, strength or intrusiveness of the hallucinations, such as watching television or listening to the radio. Not surprisingly, people hearing voices try to make some sense of their experiences, acting then as one possible mechanism for the development of unusual beliefs or delusions. A delusion is a fixedly held, usually false belief not shared by others from the patient’s cultural or social group. The core facet of a delusion is that it is a belief held onto rigidly but without evidence to support it or in the face of evidence to the contrary. Delusions often develop along very personal themes such as persecution, the patient may believe that they are the victim of some form of threat or conspiracy, or of passivity, that their thoughts or actions are being controlled by an external force, though they can develop along any theme, for instance grandiose, sexual, or religious. Many patients also develop thought disorder manifesting as distorted or illogical speech due to a failure to generate and use language in a logical and coherent fashion. It is typified by a variety of descriptive medical signs including loosening of associations, derailment, tangentiality and knights-move thinking.
Negative signs and symptoms
Negative symptoms such as social withdrawal, self-neglect, loss of motivation and initiative, emotional blunting and paucity of speech may seem less troubling to the patient, but often cause families and carers the most distress.
While not a diagnostic feature of the illness it has been recognised for some time that the majority of patients with schizophrenia experience a variety of cognitive or intellectual difficulties. These range from impaired intelligence to quite specific deficits in for example working memory and executive function. These deficits are often not immediately apparent and their impact on daily living skills or the suitability of psychological or occupational therapy programmes such as cognitive behavioural therapy, can be easily underestimated.
Clinical subtypes of schizophrenia
Psychiatrists have traditionally recognised several subtypes of schizophrenia depending upon the balance of symptoms present. Paranoid schizophrenia is typified by the presence of prominent positive symptoms specifically delusions or hallucinations often accompanied by fears of persecution, while the Hebephrenic subtype is typified by a flattened or incongruous mood, a lack of goal directed behaviour and prominent thought disorder. Catatonic schizophrenia, now rarely seen in the West is characterised by sustained evidence of abnormal motor behaviour including stupor, excitement, posturing or rigidity. Finally Simple schizophrenia was said to be associated with a significant loss of personal drive, progressive deepening of negative symptoms and a marked decline in social, academic and employment performance.
Operationalised diagnosis of schizophrenia
Two similar international systems are in use to standardise the diagnosis of schizophrenia.
- The International Statistical Classification of Diseases and Related Health Problems Tenth Revision ICD (World Health Organisation, Geneva 1993) diagnostic criteria for schizophrenia are:
- At least one of the following present most of the time for a month:
- Thought echo, insertion or withdrawal, or thought broadcast;
- Delusions of control referred to body parts, actions or sensations;
- Delusional perception;
- Hallucinatory voices giving a running commentary or discussing the patient or coming from some part of the body;
- Persistent bizarre or culturally inappropriate delusions
- Or at least two of the following present most of the time for a month:
- Persistent daily hallucinations accompanied by delusions
- Incoherent or irrelevant speech
- Catatonic behaviour such as stupor or posturing
- Negative symptoms such as marked apathy blunted or incongruous mood
- At least one of the following present most of the time for a month:
- The Diagnostic and Statistical Manual Fourth Revision DSM-IV (American Psychiatric Association) criteria for schizophrenia are:
- Two or more of the following characteristic symptoms present for a significant portion of the time for a month
- Disorganised speech
- Disorganised or catatonic behaviour
- Negative symptoms
- Social or occupational decline
- Continuous signs of disturbance for at least six months, but at least one month for the symptoms in criterion A unless treated
- Two or more of the following characteristic symptoms present for a significant portion of the time for a month
- The most commonly reported symptoms of schizophrenia are (World Health Organisation, 1973):
- Lack of insight 97%
- Auditory hallucinations 74%
- Ideas of reference 70%
- Delusions of reference 67%
- Suspiciousness 66%
- Flatness of affect 66%
- Delusional mood 64%
- Delusions of persecution 64%
- Thought alienation 52%
- Thoughts spoken aloud 50%
Epidemiology: risk factors for schizophrenia
In spite of schizophrenia’s relatively low incidence (15.2 per 100,000) (McGrath et al 2004), its prevalence remains relatively high (7.2 per 1000) (Saha et al, 2005), reflecting its tendency to start early in adult life and become chronic. The incidence of schizophrenia varies, at present rising in some populations e.g. South London (Boydell et al, 2006), while falling in others (McGrath et al, 2004). Schizophrenia typically presents in early adulthood and is rare in childhood. Men are at modestly greater risk of the disorder (McGrath et al, 2004), have an earlier age of onset than women, and also tend to experience a more severe form of the illness with more negative symptoms, less chance of a full recovery, and a generally worse outcome (Jablensky, 2000). Studies have also shown that it is more common in those born in cities, and that the larger the city and the longer the person has lived there, the greater the risk (Pedersen and Mortensen, 2001) . It seems to be more common in migrants (McGrath, 2006) despite cultural considerations, with some of the most dramatic increases seen in African and Caribbean people living in the United Kingdom, whose rates are up to 6 times those of the native white population (Fearon et al, 2006). The rates remain elevated in the children of migrants, but are not reflected in increased rates in their home country (Mahy et al, 1999). Environmental and social factors have been particularly implicated in this increased risk including racism and loss of social and family support. It is important to note that the risk of schizophrenia in migrants is greatest when they represent a smaller proportion of their local community (Boydell et al 2001).
Pathophysiology: the dopamine hypothesis of schizophrenia
Dopamine is a catecholamine neurotransmitter and a precursor of adrenaline and noradrenaline. It has been recognised for over forty years that excessive dopamine transmission in the brain’s mesolimbic system plays a key role in schizophrenia. Support for this comes from several strands of evidence (Baumeister & Francis, 2002; Seeman 2006).
- amphetamine abuse, which increases synaptic dopamine release, can produce ideas of reference, delusions and auditory hallucinations in healthy people
- small doses of amphetamine worsen psychotic symptoms in patients with schizophrenia
- the typical antipsychotic drugs can cause extrapyramidal side effects by blocking dopamine transmission in the substantia nigra, while the clinical efficacy of these same antipsychotics is closely correlated to their dopamine blocking potential
- atypical antipsychotics appear to have a lower propensity to cause extrapyramidal side effects but still bind to dopamine D2 receptors, perhaps on a more regionally selective basis
- patients with psychosis release excessive synaptic dopamine in response to an amphetamine challenge, while the magnitude of dopamine release correlates with the degree of psychotic symptoms induced.
Pathophysiology: linking dopamine to symptoms in schizophrenia
How could excessive synaptic dopamine lead a patient to psychosis and believe for instance that his neighbours are talking about him? Kapur has proposed an attractive hyperawareness theory linking dopamine dysregulation to symptom formation (Kapur, 2003). Kapur pointed out that one of dopamine’s roles is to attribute personal importance or ‘salience’, converting a neutral mental representation into one with personal significance and so grabbing our attention. Kapur’s theory proposes that in psychosis, excessive dopamine adds salience to mundane and insignificant thoughts or perceptions. In this way, everyday events, eye contact with a stranger, a trivial sound, or the comments of a newsreader are given personal importance and attract our attention. Delusions may then develop in an attempt to make some sense of an apparently changed world in which personally important events seem to be going on around the patient all of the time.
Pathophysiology: the NMDA and glutamate hypothesis of schizophrenia
Although the dopamine theory of schizophrenia is supported by the correlation between the clinical potencies of the antipsychotic drugs and their affinity for the dopamine D2 receptor, there are inconsistencies that do not support the theory. While antipsychotic drugs can often control the positive symptoms of schizophrenia such as hallucinations and delusions in the acute setting, the same antipsychotics tend to be less effective in patients who have been symptomatic for many years. In addition, the antipsychotics are much less effective at addressing negative symptoms or the cognitive impairments, such as impaired memory seen in many patients.
The N-methyl-D-aspartic acid (NMDA) receptor hypofunction hypothesis developed in part to explain some of these inconsistencies, including why schizophrenia is associated with subtle structural brain changes and the prominence of negative symptoms and cognitive impairment (Javitt & Zukin, 1991) in the disorder. Support for the NMDA theory comes from several lines of evidence:
- Ketamine and phencyclidine (PCP), both NMDA receptor antagonists can induce a clinical state indistinguishable from schizophrenia including both positive and negative symptoms, and can worsen symptom control in clinically stable patients.
- The pro-psychotic effects of phencyclidine and ketamine can be effectively treated by haloperidol (Giannini et al, 2000).
- Ketamine administration is associated with increased cortical glutamate turnover particularly in the anterior cingulate gyrus and loss of GABAergic (γ-aminobutyric acid) interneurones in the hippocampus and thalamus, changes that are partially reversible with treatment with haloperidol or clozapine
Pharmacological attempts to modify the glutamate system therapeutically in schizophrenia have met with mixed results (Patil et al. 2007) and could be confounded by interactions with the dopamine system (Seeman, 2008)
The causes of schizophrenia: genetic and environmental factors
Schizophrenia is a complex clinical disorder. Its single greatest risk factor is a positive family history. While the lifetime risk in the general population in just below 1%, it is 6.5% in the first-degree relatives of patients (Kendler et al, 1993), and rises to over 40% in the monozygotic (genetically identical) co-twins of affected patients (Cardno et al, 1999), suggesting a link between the genetic proximity between the relative and patient and risk. Furthermore one small but landmark study has suggested that the risk is transmitted equally to the offspring of the well and ill twins from monozygotic discordant pairs, seemingly independent of whether they are were affected by the illness status or not.
After many years of failure, there has been some recent success identifying genes that increase the risk for schizophrenia. In 2002, the deCODE genetics group in Iceland identified a haplotype in the Neuregulin 1 (NRG1) gene (Stefansson et al, 2002) which appeared to double the risk of illness, a result later replicated in Scotland and Wales, South Africa and China. Other susceptibility genes that have recently emerged are Dysbindin (DTNBP1), and DISC1. It is generally believed that there are many risk genes each of small effect and each relatively common in the general population. Patients probably inherit several risk genes which interact with each other and the environment to cause schizophrenia once a critical liability threshold has been crossed. In contrast, Crow (Crow, 2000) has proposed a genetic model based on a single genetic mutation directly linked to the speciation event that gave rise to Homo Sapiens, cerebral asymmetry and our capacity for language.
While concordance rates (the likelihood that both twins are affected) approach 50% in monozygotic twins the fact that they are not 100% implicates epigenetic and perhaps environmental factors. A meta analysis has shown that patients with schizophrenia are more likely to have experienced obstetric complications, in particular premature birth, low birth weight and perinatal hypoxia (Canon et al, 2002). They are also more likely to have been born in late winter and early spring, possibly reflecting intra-uterine viral exposure. These early environmental hazards could act to subtly deviate early brain development.
In adulthood different environmental stressors act; associations are seen with social isolation, migrant status, substance misuse and urban life (Boydell et al, 2004), this remains the case even when life events attributable to the incipient psychosis itself are excluded. Historically certain parenting styles were considered to increase the risk of the illness in children, however it seems that the way parents raise their children does not have a major impact on future vulnerability. On the other hand families may have an important role to play in the course of the illness once it develops; patients with supportive parents have fewer and less severe relapses than those with critical or hostile relatives. Collectively these risk factors point to an interaction between biological, psychological and social risk factors driving increasingly deviant development and finally frank psychosis (Broome et al 2005, Howes et al, 2004).
Drug abuse and schizophrenia
Stimulants like cocaine and amphetamines are capable of inducing a picture clinically identical to paranoid schizophrenia, and more recent reports have also implicated cannabis. There is overwhelming evidence that patients with established schizophrenia smoke more cannabis than the general population. Now well conducted cohort studies like that from Dunedin in New Zealand (Arseneault et al, 2002) specifically indicate that early cannabis use, long predating the psychotic symptoms, increases the future risk of schizophrenia four fold while a meta-analysis of prospective studies reported a doubling of risk (Henquet et al, 2005). This effect is robust, even after controlling for a self medication effect (Henquet et al, 2005), undermining the suggestion that this early cannabis use is primarily an attempt to alleviate anxiety or distress actually caused by the developing illness. Of course, only a small proportion of people who use cannabis develop schizophrenia, just as only a proportion of those who misuse alcohol develop cirrhosis. This probably reflects a genetically determined vulnerability to the environmental agent. Indeed, there have been suggestions that variations in the dopamine metabolising COMT gene influence the vulnerability to develop psychosis in people who use cannabis (Caspi et al, 2005).
Neuropathology: structural brain changes
Pathological studies confirm that the total ventricular volume is sometimes enlarged in severe schizophrenia and cortical volume decreased. While the pathology does not seem to be focal, certain regions seem to be more prone to tissue volume loss including the hippocampus and prefrontal cortex. This volume loss seems primarily underpinned by dendritic abnormalities, without gliosis and possibly preferentially in the glutamatergic neurones of the hippocampus.
Modern neuroimaging techniques offer an unparalleled opportunity to explore the structure and function of the brain in schizophrenia. A wealth of structural imaging evidence has accumulated, confirmed by a recent meta-analysis that support the neuropathological conclusions that patients with severe schizophrenia have smaller whole brain volumes and larger lateral ventricles (Steen et al, 2006). Exactly what causes the abnormalities is contentious with some suggesting that genetic factors and early environmental insults contribute, others saying that they are part of the disease progression and yet others that antipsychotic drugs may make a contribution. This volume loss seems to particularly affect the frontal and temporal lobes. Functional imaging studies have now begun to identify the biological underpinnings for some of the well recognised cognitive deficits found in schizophrenia, and to define the anatomical and functional basis of psychotic symptoms such as auditory hallucinations (Shergill et al, 2000).
Is early recognition of schizophrenia important?
The average duration of untreated psychosis (DUP), the time between first psychiatric symptom and starting antipsychotic treatment, is in the region of 1-2 years in many Western countries (Larsen et al, 2001). A systematic review and a meta analysis have shown that the longer this period, the worse the outcome (Perkins et al, 2005, Norman et al, 2005). The idea that reducing the duration of untreated psychosis will then be reflected in improved long term outcome is both unproven and contentious but has lead to a recent massive expansion in ‘First Episode Psychosis’ services in many countries. Whether or not this early intervention proves to be able to alter the future course of the illness (Marshall & Rathbone, 2006), common sense and doctors’ obligation to reduce suffering imply that patients with psychotic symptoms should be identified and offered suitable treatment as quickly as possible.
Current national United Kingdom (National Institute of Clinical Excellence, NICE) treatment guidelines (National Institute for Clinical Excellence, 2002) recommend considering an oral atypical antipsychotic in low doses for the first line pharmacological treatment of a patient with acute schizophrenia. The atypical antipsychotics have different side-effects to typical antipsychotics but these can be just as debilitating. Certainly, except for clozapine, well conducted randomised controlled trials have shown that they are no more effective than the older typical drugs (Jones et al, 2006, Lieberman et al, 2005). Typical drugs are more likely to causes neurological motor side effects in particular parkinsonism, bradykinesia, tremor and rigidity and tardive dyskinesia and specific hormone abnormalities such as hyperprolactinaemia (elevated prolactin), particularly those with a narrow therapeutic index such as haloperidol. However for patients with established illness who already take a typical antipsychotic and who are clinically well without troublesome side effects, changing to an atypical is not indicated (National Institute for Clinical Excellence, 2002). For those patients on typical antipsychotics with extrapyramidal side effects, clinicians should consider a change to an atypical antipsychotic. Intermittent dosing regimens and drug holidays to reduce side effects are not recommended due to the increased risk of relapse. Clinicians should utilise the lowest effective dose of antipsychotic possible, while concurrent use of two or more antipsychotics should be limited. Depot preparations are usually offered where a patient finds it hard to remember to regularly take their medication. Meta analysis has shown that clozapine is the treatment of choice for the significant proportion of patients (20-30%) who are treatment resistant (Wahlbeck et al, 1999). This is defined as a failure to respond to two or more antipsychotics, one of which should be an atypical, at adequate dose for a minimum of 6-8 weeks, and once confounding factors such as concordance failure or substance misuse have been excluded. Clozapine has a mandatory requirement for regular full blood count monitoring to prevent agranulocytosis which occurs in less than 1% of cases. It is the only antipsychotic with a convincing body of evidence to support its efficacy in reducing both positive and negative symptoms in those with treatment resistant schizophrenia.
A range of effective psychological treatments are available, and can be harnessed to ameliorate symptoms, improve functioning and prevent relapse. Unfortunately their availability is often limited by a lack of trained therapists. Systematic reviews show that cognitive behavioural therapy (CBT) seems to be effective in reducing persistent symptoms and improving insight (Gaskell and the British Psychological Society, 2003, Jones et al, 2006), NICE guidelines recommend that it should be provided for a minimum of ten sessions over three months.
Family therapy provides support and education for families that have close contact with patients. It focuses on improving communication between family members, raising the awareness of all parties and reducing distress. It has been shown to be effective in reducing relapse rates, admission rates and symptom levels, improving treatment compliance and reducing the burden upon carers. Psychoeducation has similarly been shown through systematic review to reduce relapse and readmission rates while potentially being highly cost efficient. Other therapies with less robustly established evidence include cognitive remediation therapy and social skills training; while psychodynamic psychotherapy is not supported by any evidence (Malmberg et al, 2007).
Long term treatment
Once a patient has recovered from an acute episode of schizophrenia current NICE guidelines recommend that they should remain on prophylactic doses of antipsychotic for two years and continue under the supervision of specialist services. After that point if they remain well and symptom free, the dose of antipsychotic can be very gradually reduced, and the patient carefully followed up to detect any signs of relapse, if any signs re-emerge then the dose should be increased again until they disappear.
Vigilance and persistence are central to ensuring that patients with schizophrenia receive good quality physical health care see. Each patient should be offered regular physical health checks tailored to their needs. Special attention should be paid to screening for endocrine disorders, hyperglycaemia and hyperprolactinaemia, cardio-vascular risk factors such as smoking, hypertension and hyperlipidaemia and side effects of antipsychotic medication particularly neurological, cardiovascular, and sexual. Some patients will inevitably have to be exclusively managed in secondary care, guideline criteria for those for whom this is most suitable include poor treatment compliance, poor treatment response, ongoing substance misuse, increase in risk profile.
Evidence suggests that the common perception that schizophrenia is necessarily associated with a poor prognosis can be discarded. Over 80% of those suffering their first episode of psychosis, will make a recovery. Unfortunately, less than 20% will never have another episode (Robinson, 1999). While schizophrenia for many patients represents a life long vulnerability to recurrent episodes of illness; a significant proportion of patients will experience few relapses and make a good functional recovery. Poor premorbid adjustment, a slow insidious onset and a long duration of untreated psychosis, together with prominent negative symptoms tend to be associated with a poorer prognosis (Perkins et al, 2005 , Malla et al, 2005). By the same token an acute onset, an obvious psychosocial precipitant and good premorbid adjustment all improve the prognosis. While the signs and symptoms of schizophrenia tend to improve as the person ages, there is a risk of suicide, of the order 5-10% of individuals with the disease. Altogether, schizophrenia predisposes the individual to an increased mortality and reduced life expectancy. In addition, about 2-5% of individuals with schizophrenia can be violent, and family members must be aware of this. The majority of those with schizophrenia, of the order of 70%, cannot hold onto jobs in the general society, and only 10% of individuals with schizophrenia can take care of children.
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