schizophrenia was coined by Eugen Bleuler in 1908 and was intended to describe
the separation between personality, thinking, memory and perception. The word
schizophrenia comes from the Greek roots ‘schizein’ (to split) and ‘phren’
(mind). Bleuler described the main symptoms as 4 As: flattened Affect, Autism,
impaired Association of ideas and Ambivalence.2 Bleuler realised
that the illness was not a dementia as some of his patients improved rather
than deteriorated and hence proposed the term schizophrenia instead.
Kurt Schneider took
a more phenomenological approach. He determined that in the absence of an organic
cause, the ‘first-rank symptoms’ were diagnostic of schizophrenia. These
descriptions have been highly influential, although on their own they are not
diagnostic of schizophrenia.
contributions have focused on etiology and potential types of schizophrenia:
Crow ascribed a etiological relevance to the pattern of symptoms in
schizophrenia, describing how positive symptoms were associated with more
neurochemical changes while negative symptoms were evidence of structural brain
changes. Crow and his colleague Eve Johnson were the first to show brain
changes in CT-scans of patients with schizophrenia. Crow described a type1/type
2 classification of schizophrenia.
Type 1: More florid
presentation; positive symptoms due probably to dopamine dysregulation with
good response to antipsychotics.
Type 2: More
chronic; predominantly negative symptoms associated with enlarged brain
ventricles and cortical tissue loss with poor response to antipsychotics.
Liddle in England described 3 syndromes of schizophrenia: (1) a positive
syndrome with reality distortions characterised by delusions and hallucinations
(2) a negative syndrome (3) disorganisation syndrome characterised by positive
formal thought disorder, inappropriate affect and poverty of speech.
Murray in England and Daniel Weinberger in the USA have emphasized the notion
that schizophrenia is a disorder of faulty brain development.3
Andreasen in the USA has proposed that schizophrenia is a disorder of brain
dysconnectivity. She has ascribed a series of pattern of brain abnormalities
that are associated with schizophrenia.4
The stigma of schizophrenia
remains an enigmatic condition and because of its association with violence, it
remains a highly stigmatising condition. One study evaluated the ‘potential
discriminatory experiences’ among 732 patients with schizophrenia in 27
countries: 5 positive discrimination was rarely noted, and the
majority of patients had experienced some form of negative discrimination. Over
70% of patients did not wish to reveal their mental illness in public. Patients
felt they were discriminated against in getting (29% of patients) and keeping
(29%) a job, and most patients (64%) said they would decline to even apply for
a job because of the certainty of discrimination. Stigma is a pervasive
Causes of schizophrenia
exact causes of schizophrenia are not known.6
believed to run in families and is associated with birth complications, head
injury, epilepsy and drug abuse. Cannabis abuse raises one’s risk for
schizophrenia by 2 to 4.5 fold.
have shown abnormalities on several chromosomes (eg chromosome 5, 8,11 ,13,
22).7 More recent studies have focused on the search for abnormalities
in genes or their related proteins that are involved in development (eg
dysbindin, neuroregulin, synaptosome-associated protein of 25,000 Da, brain
derived neurotrophic factor (BDNF).8
In addition to the
anticipated deletions in the region of chromosome 13 that has already been
implicated in velocardiofacial syndrome (a genetic condition in which 30% of
patients develop a psychosis that is indistinguishable from schizophrenia), the
study found small deletions on chromosomes 1 and 15.9 Although these
variants are rare and represent deletion of sections of DNA, they substantially
increase the risk of schizophrenia.
2. Birth and other environmental factors
One of the most
reproducible findings in schizophrenia is that affected patients are far more
likely to have been born in the first three months of the year- the so called
‘season of birth effect’.A
study examined BDNF from umbilical cord and maternal blood samples collected in
a large cohort of people who later developed schizophrenia. It was observed that
BDNF was significantly decreased in those patients who experienced fetal
hypoxia, further emphasizing the importance of obstetrical complications as an
etiological event in schizophrenia.10
study found that mothers who were exposed to the death of a relative during the
first trimester of pregnancy were 1.67 times more likely to have offspring who
later developed schizophrenia or related psychoses.11 There are
several lines of evidence that point to the vulnerability of the fetal brain to
the physiological impact of stress, especially the effects of glucocorticoids
early in brain development.
with schizophrenia frequently abuse alcohol or illicit drugs. This occurs
throughout the illness. This relationship is also often seen at the time of the
person’s first presentation of psychosis, raising the vexing questions as to
whether substance abuse can cause schizophrenia, whether it is some phenomenon
or result of people self medicating to cope with the symptoms of schizophrenia.
There is considerable evidence linking social adversity at the neighborhood
level and evidence linking lower social bonds (social cohesion) in communities
with an increased risk of first episode schizophrenia.12 It is the
areas in which people live and interact with others that are important, rather
than the country level.
abnormalities and the neurodevelopmental hypothesis
recent studies have shown deficits in the expression of neurodevelopmental
genes and BDNF in several post-mortem collections. Imaging studies of patients
show a range of brain abnormalities: smaller cortex overall, preferentially
less grey matter than white matter, enlarged ventricles (especially the lateral
ventricles), enlarged caudate nucleus and putamen, smaller thalamus and
decreased size of temporal lobes (especially reduction in the hippocampal
have shown that hearing voices is associated with overactivity in the left
temporal lobe regions. Also, both MRS studies of first episode patients and
longitudinal MRS studies reveal a decrement in N-acetyl aspartate (NAA), a
putative marker of neuronal intensity. Cortical vulnerabilities may become
exposed at adolescence when the brain shows heightened plasticity. Drugs or
stress during adolescence may be other critical events.
direct opposition to the brain imaging evidence that supports the
neurodevelopmental hypothesis in schizophrenia, other long term imaging studies
report a progressive loss of brain tissue.13 MRI studies in patients
with first episode schizophrenia who are then rescanned later demonstrated that
progressive brain changes occur in patients who relapse and are more
symptomatic. A more recent study tested the relationship between the
vulnerability in the expression of BDNF polymorphism and progressive brain
tissue loss on MRI. Their results showed that patients who possess the met-met
allele had the most reduction in frontal lobe tissue. Interestingly, patients
who received most medications had the most frontal tissue loss, an effect that
proved independent of BDNF polymorphism status.14
4. Other causes of schizophrenia
has been proposed that, through vulnerability to oxidative damage, there are
free radical effects that impact on cellular processes, especially
mitochondrial, prostaglandin and cell membrane functioning. This hypothesis has
been studied in a variety of ways, including plasma and CSF assays for
breakdown products of oxidative stress, brain imaging of neurochemistry using
MRS, and treatment studies using vitamin E or fish-oil products. One study
suggested that schizophrenia might be caused by irritation of the brain that
could occur from middle ear disease.15 The study demonstrated that
people who had middle ear disease were over 3.6 times more likely to have a
later diagnosis of schizophrenia (or over 4 times more likely if the middle ear
disease was on the left side).
5. Brain chemistry
activity of the dopamine neurotransmitter system is the most compelling
neurochemical abnormality in schizophrenia.16 Funtional
brain-imaging studies show excess of dopamine in the brain of patients when
they are acutely psychotic.
and Statistical Manual of Mental disorders in USA and the 10th
revision of the International Classification of diseases and related Health
problems in Europe emphasize on a Schneiderian view of the condition being
characterised by delusions, hallucinations, disturbances of speech, restricted
affect and emotionality and impairments of thinking. It is important to
differentiate it from other psychotic conditions, which it can resemble in
presentation. (Table 1)
Table1:Conditions that resemble schizophrenia
Organic related psychoses
can be ill for many months or even years before they come into treatment, and
there is increasing evidence linking the duration of untreated psychosis with
poorer outcome, 17 now confirmed in systemic reviews. There are a
variety of reasons as to why this may be so, including neurobiological concepts
of kindling and the strengthening of neural circuits involved in
psychopathology with time, psychological notions linking continued trauma from
frightening psychotic experiences leading to further morbidity and social
explanations of increasing loss of social capital (education, family ties,
occupational and vocational opportunity). Early intervention through an effort
to identify people with prodromal symptoms or early fragments of schizophrenia
syndrome, so called ‘at risk mental states’ (ARMS), have begun. Some studies
have suggested that giving antipsychotics (or even antidepressants alone) to
these patients might forestall a psychotic break. However, there are serious
ethical considerations with this approach.18
Treatment and general considerations
drugs work best on positive symptoms but have generally limited impact on
negative or cognitive symptoms. This is a real drawback since in the long run,
negative and cognitive symptoms tend to be more disabling. It is very important
to appreciate that medications alone are ineffective and that patients need
counselling, support, family involvement, care advice and job skills training.
Presently, there is considerable variability in the access to care and in the
medication practices (eg variability between practitioners with under dosing of
medications, patients staying too long on medications and patients receiving 2
or more antipsychotics simultaneously).
patients also help themselves by organizing into self-help groups
(Schizophrenia Anonymous) or by helping each other as trained peer counselors
(peer support specialists). Patients also turn to the Internet for education,
support and resources. A European study showed how patients could use a
web-based self monitoring system to detect when they were relapsing and to
communicate thus more clearly with their psychiatrists. Antipsychotic
medications are truly the bedrock of treatment. Medication choice remains a
trial and error process, with patient’s risk for particular side effects
associated with any given medication generally being taken into consideration.19
how antipsychotics work remains a mystery. Most evidence points to effects on
blocking dopamine receptors in the mesolimbic system. For first generation
antipsychotics, it has been proposed from PET and SPECT studies that the drugs
need to achieve at least 60% occupancy rate of dopamine receptors in order to
be clinically effective. The dilemma is that at 70% occupancy rate
of dopamine receptors, these drugs cause muscle side effects.20 Some
drugs, such as haloperidol, are more potent and can saturate the dopamine
receptors at relatively low doses. Other antipsychotics are low-potency agents
and are generally given at higher doses. Other antipsychotics are low potency
agents and are generally given at higher doses.
generation antipsychotics namely risperidone, olanzapine and ziprasidone bind
to dopamine D2 receptors at proportionately lower rates than first generation
antipsychotics and at comparatively lower rates compared to each other
(risperidone is the most potent in D2 binding among these 3 drugs). Clozapine
generally reaches only a 40-50% D2 occupancy rate, and giving more medication
will not exceed this rate, phenomenon known as ‘glass-ceiling effect’.
Quetiapine has an even lower rate, an average of 28% of D2 binding. Kapur and
colleagues have proposed the elegant ‘kiss and run theory’ to explain that
quetiapine appears to saturate D2 receptors.21 In contrast,
Aripiprazole virtually saturates D2 receptors with a 90-95% occupancy rate,
even at low doses.22 It functions more as dopamine agonist when the
synapse has insufficient dopamine and vice-versa.
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