SCHIZOPHRENIA - Current Thinking
Schizophrenia is nowadays generally acknowledged to be a brain disease. Pyschosocial stressors are important and remedial determinants of relapse and possibly of timing of the first episode, and may even determine whether the disorder occurs at all. It seems more and more likely that a specific set of biological predispositions is necessary (even if not sufficient) for the disease to occur.
Given that the concordance for the disease in monozygotic twins is of the order of 40 percent (as compared with about 15 percent for dizygotic twins), then clearly both genetic and environmental factors are important.
Progress in this area is traditionally very slow. Schizophrenia research has the reputation of being a graveyard of researchers and their hypotheses, from the orthomolecular theories of Nobel Laureate Linus Pauling to the double blind hypothesis of Gregory Bateson, and many others. There is at least the illusion of progress at present and in part this may follow on from two major developments.
The first is the process by which more rigorous diagnostic criteria for the disorder have been refined over the past 20 years or so.
There may still be problems with the definition, as we are probably applying the term schizophrenia to a mixed bag of unrelated conditions. If different underlying mechanisms produce a similar clinical picture we cannot expect research to produce any particular facts about the broad range of cases and progress would be made by spinning off more homogeneous diagnostic entities. Even so, diagnostic practice is now more consistent and logical than it has ever been.
The second development is that of modern neuroscience. The discovery that certain medications could ameliorate psychotic symptoms and then evidence that this benefit was caused by dopamine receptor blockade ushered in the modern age of schizophrenia research and, of course, treatment. Thus was generated the dopamine hypothesis of schizophrenia which is still with us in modified form but looking increasingly unlikely as 'the' explanation of schizophrenia.
Such thinking enabled psychiatric research to link with the wider medical research community and now advances in other areas of medicine, especially neurology and other medical subspecialties such as immunology and endocrinology, are a fertile source of hypotheses and technology for schizophrenia researchers.
It may be that progress in a scientific field requires a common understanding of the nature of the problems to be solved (this is one reading of Thomas Kuhn's ideas). The major unifying hypotheses in current schizophrenia research are:
- The neurodevelopmental theory, in other words that schizophrenia is a neurodevelopmental disease (rather than a form of dementia as the great German and French psychiatrists of a century ago thought), evidence for which continues to accumulate, and
- The stress-diathesis model, the idea that symptoms are the result of an interaction between the inherent disposition of the person and their environment.
The cross sectional and longitudinal picture: DSM IV diagnostic criteria paraphrased:
The characteristic symptoms are two or more of the following (lasting at least most of a month unless specifically treated:
- Delusions (incorrect beliefs, not based on adequate evidence and not amenable to reasoning and not in keeping with the person's culture).
- Hallucinations (experiences not based on the real world).
- Disorganised speech (also called thought disorders)
- Grossly disorganised or catatonic behaviour
- Negative symptoms, such as lack of emotion or volition, or reduced communication.
However, if the two highly typical symptoms of either so-called bizarre delusions or auditory hallucinations are in the form of either a running commentary or two or more voices conversing with each other, then no other characteristic symptoms is required.
In addition to characteristic symptoms, there must be a deterioration in occupational functioning, interpersonal relationships or ability to care for oneself. The overall duration of symptoms of the disorder must be at least six months, i.e. at least one month of characteristic symptoms as above plus prodromal or residual symptoms (such as functioning deficits, negative symptoms, or attenuated forms or other characteristic symptoms).
Other criteria required the exclusion of various other disorders:
- Schizoaffective disorder (in which psychotic and mood symptoms are mixed).
- A mood disorder such as depression with accompanying psychotic symptoms.
- A psychotic disorder secondary to substance use (e.g. the use of PCP or LSD).
- Psychosis due to a general medical condition (e.g. psychosis due to basal ganglia calcification).
- A simple pervasive developmental disorder such as autism.
Subtypes are recognised (these are not particularly useful in practice):
- Paranoid type: delusions and hallucinations but relative preservation of cognitive functioning and affect.
- Disorganised type: disorganised speech and behaviour with inappropriate or flat affect and no catatonic symptoms.
- Catatonic type: prominent catatonic features, namely two or more of motoric immobility or stupor; excessive purposeless motor activity, extreme negativism or mutism, posturing, stereotypes, mannerisms or grimacing; echolalla or echopraxia (copying another's speech or actions in a seterotyped way). It should not noted that this subtype is now relatively rare.
- Undifferentiated type: all the rest.
Notes on the above:
Bizarre delusions are clearly implausible, not understandable and do not derive from ordinary life experiences. Typically such delusions are very unusual, such as the belief that one is the son of Queen Victoria by an alien, as opposed to nonbizarre delusions such as being wanted by the SIS (which might be true). Characteristic examples include thought withdrawal (the belief that someone else can remove one's thoughts from one's mind), thought insertion (the belief that someone else can put thoughts into one's mind - in a very literal sort of way), thought broadcasting (the thought that someone else is literally reading one's mind) and delusions of being controlled (e.g. that others literally force my body to perform actions or experience emotions against my will).
Hallucinations are typically auditory, but also occur in any other modality. Visual hallucinations are more characteristic of organic states if occurring alone, and olfactory or gustatory hallucinations in particular should stimulate a search for organic pathology, particularly temporal lobe epilepsy. In addition to the auditory hallucinations noted above, hearing one's own thoughts out loud (before, during or after one has the thought) is also highly suggestive of schizophrenia.
Derailment (the speaker changes topic, sometimes halfway through a sentence, without being aware of this) and thought blocking (the flow of thoughts suddenly comes to an end part way through a sentence and the topic cannot be retrieved) are particularly characteristic of the thought disorder associated with schizophrenia.
The disorganised behaviour may include frequent distraction by or discussions with the "voice".
Over the past two decades researchers and clinicians have often divided the characteristic features of schizophrenia into psychotic symptoms (the Type 1 syndrome of Crow or positive symptoms of Andressen - following Hughlings Jackson) and the combination of lack of motivation, emotional blunting, and lack of spontaneity of thought and action (Crow's Type II syndrome or Andressen's negative symptoms).
More recently this simply binary division has been considered inadequate and three dimensions of psychopathology have been proposed by authors such as Liddell:
- Psychotic dimension (like positive symptoms): delusions and hallucinations
- Disorganised dimension: disorganised speech or behaviour, or inappropriate affect
- Negative dimension (like negative symptoms): affective flattening, avocation, and alogia.
Schizophrenia affects about 1 % of people over the course of their lives. The sex ratio is equal or there is a slight preponderance of males. The usual age of onset is 15 to 25 in males, slightly later in females, but it may occur at any age (DSM IV stipulates no upper age limit for onset). Early onsetting schizophrenia (before adolescence) seems a relatively severe form.
Aetiology and pathogenesis
As alluded to in the introduction, the relevance of biological factors is supported by many lines of evidence so that there can be little doubt that schizophrenia is a group of brain diseases, albeit of obscure aetiology. It has been postulated that schizophrenia is a neurodevelopmental disorder in which a fixed brain lesion early in life becomes evident as psychiatric symptoms in late adolescence and early adulthood following the latest stages of myelination or other brain changes. This thesis rests on the clinical maxim that the manifestations of a brain lesion vary with the state of brain development. Some relevant considerations are as follows.
A. Genetics. Pedigree, twin and adoption studies provide support for heritable factors. Particularly convincing are the adoptive studies of Heston and Kety et al (both published in 1966) which show biological rather than adopted relatives are at increased risk for the disorder. Concordance rates are increased in monozygotic, as compared to dizygotic, twins. The risk for first-degree biological relatives is 10 times the risk in the general population. Linkage studies have so far only come up with a few false leads, but methodology is continuing to improve and several areas of the genome are currently undergoing intensive scrutiny.
B. Environmental factors. What sort of environmental agents might cause schizophrenia (recognising that a variety of insults may cause a similar clinical picture)? One recently recognised phenomenon is the occurrence of an increased incidence of schizophrenia in a cohort of adults whose mothers were in the second trimester at the time of the so-called Dutch Hunger Winter of 1944. So inadequate nutrition might be one factor. Another is the hypothesis that schizophrenia might be associated with maternal viral infections, especially, again, in the second trimester. This seems to be true in relation to some influenza epidemics in some populations but not in others.
C. Biochemical. The dopamine hypothesis that schizophrenia is a hyperdopaminergic state, as suggested by the efficacy of dopamine blockers and the psychotomimetlc effects of amphetamine, is too simplistic. The possibility of overactivity of the mesolimbic pathway remains viable and there is now known to be a range of dopamine receptor subtypes but research into these has so far not brought insight into the cause or pathophysiology of schizophrenia. The success of medications with both dopominergic and saratonergic effects has led to more complex biochemical hypotheses.
D. Structural pathology. The evidence can be divided, for convenience, into imaging and pathological studies:
Structural brain changes as seen on MRI and other forms of brain imaging include enlarged cerebral ventricles and widened cortical suici, a reduction in the overall amount of cortex, and this might be especially evident in the temporal lobes of the brain, and a smaller amygdala.
There are also frontal lobe abnormalities on some measures (e.g. hypometabolism on PET scans), but this might be due to distant effects of dysfunction elsewhere in the brain. Neurological soft signs are frequent in children who later develop schizophrenia. These changes seem to be present early in the course of the illness (predating onset of the characteristic symptoms) and generally to be relatively static, although progression in a subset of cases cannot be ruled out at this stage.
There are suggestions that psychomotor poverty might relate to a reduction in left prefrontal grey matter and reality distortion may be linked to medial or lateral temporal lobe abnormalities. One exciting recent finding, which requires further exploration but shows the power of modern neuroimaging approaches, is that auditory hallucinations ('voices', one of the most striking features of most cases of schizophrenia) are associated with activation of the primary and association auditory cortex. Thus, the perception of auditory hallucinations utilises the same brain mechanisms as the perception of normal speech.
The next question is then, why and from where does this abnormal input arise? There are no clear answers but middle temporal cortex and subcortical regions may help determine whether 'inner speech' is turned into the perception of 'voices' by inhibiting or facilitating the activation of auditory cortex.
The main brain areas that are being examined microscopically include the dorsolateral prefrontal area, the cingulate gyrus and the mesial temporal area. There is evidence of disorganised neuronal cytoarchitecture in the hippocampus and the loss of the usual obvious layering of neurones in the deep layers of the adjacent entorhinal cortex; these neurones may instead show irregular clumping. One of the most important clues here is the absence of a gliotic reaction. Reactive gliosis does not occur before the end of pregnancy, so this is evidence that if schizophrenia is at least in part caused by environmental agents then these must occur before the end of pregnancy.
E. Toxicological. It is unclear whether true blue schizophrenia is ever 'caused' rather than unmasked or precipitated, by substances of abuse. The similarity between substance-induced psychotic states, particularly those involving hallucinogens such as d-LSD or arylcylohexylamines such as phencyclidine, has led to hypothesis regarding endogenously produced psychotoxins but the evidence for this is scanty.
One possibility is the defective filter theory of Broadbent; that those suffering from schizophrenia cannot filter out irrelevant information and thus processing mechanisms are overwhelmed. There is some evidence for an attentional deficit in schizophrenia along these lines.
There is no evidence that the 'schizophrenogenic mother' exists. There is some evidence of parental conflict, unusual thinking patterns and abnormal communication in some families of patients with schizophrenia but it is very difficult to exclude abnormalities due to schizophrenic spectrum disorder in near relatives and the effects on the family of a family member with schizophrenia. What is clear is that a high level of expressed emotion (E.E), consisting of expressed criticism, hostility and over-involvement in the social environment is a risk factor for relapse. This is the case not only for schizophrenia but for most other disorders studied (including non-psychiatric disorders) and applies whether the patient is in the family setting or some other institutional environment.
Schizophrenia appears to be, on average, less disabling in some cultures, such as in India. It should be noted that diagnostic practices also effect the prevalence and prognosis of the disorder (thus the Soviet penchant, now changing, for 'sluggish schizophrenia' with its political misuses contributed to overdiagnosis, whilst the DSM IV in which five months and 20 days of disorder only qualifies one for schizophreniform disorder has narrowed the diagnosis rather more than its traditional usage).
Biological antipsychotic agents are the mainstay of treatment. Depot preparations are often required to enhance compliance. The development of so-called atypical antipsychotics has reduced the proportion of patients with treatment refractory forms of the illness. The prototype was clozapine and this may still by the most effective. This medication preferentially blocks dopamine receptors in the mesolimbic system (D4 receptors rather than the D2 receptors in the nigrostriatal system), so has a lower rate of causing parkinsonism, tardive dyskinesia (a movement disorder particularly involving the lips, tongue and mouth but also other areas caused by long term antipsychotic use) and dystonia. It also blocks some serotonin receptors and this is thought to possibly contribute to its increased efficacy over 'typical' neuroleptics.
The main problem with clozapine is a 1% risk of agranulocytosis (the bone marrow fails to produce certain white blood cells, leaving the body highly vulnerable to infection) so its use requires frequent blood counts and discontinuation if the white count drops. Some of the other atypical antipsychotics such as risperidone (rapidly becoming the antipsychotic of choice in first episode psychosis world wide) and olanzapine also have an effect on serotonin receptors.
Psychosocial interventions include psychoeducational approaches to the patient and family and general support. Management should be individualised and comprehensive. This may include social skills training (to help compensate for the negative symptoms of chronic schizophrenia), assertion training and other behavioural interventions for the patient, and efforts to reduce expressed emotion and reduction in the burden of care (both objective and subjective) for the family.
One package is Falloon's Behavioural Family Management approach which aims to correct defects in personal and family interactions using behaviour analysis, education and problem solving strategies.
An area of current innovation and research is the use of cognitive-behavioural therapy both to reduce the post-traumatic and neurotic-like affects of psychotic episodes (which are highly unpleasant and disruptive experiences) and also to diminish the intensity of chronic, neuroleptic refractory delusions.
Management involves more than treatment; it should also be about helping the individual achieve adequate quality of life. Thus some individuals will require good quality sheltered accommodation (asylum in the true sense) for the remainder of their days, others opportunities for sheltered occupation and organised leisure activities. The general aspects of management can include the provision of adequate medical care (the chronically psychotic have an increased risk of all kinds of health problems), the provision of workers dedicated to supporting the patient, (alongside the traditional treatment structures) and encouraging the input of patients and their families into all aspects of the provision of care (whilst maintaining adequate privacy - this is sometimes a particularly difficult balancing act). This will include encouraging the participation of consumer representatives and liaison with self-help groups and organisations of caregivers such as the Schizophrenia Fellowship.
Some patients will require committal under the Mental Health Act from time to time to enforce treatment because of danger to themselves or others, and a few individuals may require long term compulsory treatment but this is fortunately becoming less common with more effective treatments.
Clompi (in the 1970s so the definition of schizophrenia was somewhat different) suggested a favourable outcome in 49%, unfavourable in 42%, and the remainder uncertain or unstable.
More recent studies indicate only up to 26% recover, 40% suffer recurrent episodes and 36% are chronically psychotic. A poorer outcome is correlated with the following factors: poor pre-illness adjustment, gradual onset, no acute precipitants, delays in treatment, prolonged presence of positive symptoms, male gender, minimal mood disturbance, a family history of schizophrenia, poor functioning between episodes of positive symptoms, residual symptoms and structural brain abnormalities or neurological dysfunction.