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Schizophrenia

Schizophrenia: The latest trends

1Nemowtee Anita Ramdinny,2 Netranee Anju Ramdinny-Purryag

Consultant Psychiatrist St. Jeen Pharmacy, Mauritius1, 2

Abstract

Schizophrenia is the most severe of all the mental illnesses although fortunately, it is not as common as other conditions like depressive and anxiety disorders. Schizophrenia clearly runs in families but however, the genetic basis is poorly understood. Many patients do not have a family history of psychosis. Treatment for schizophrenia needs to be a comprehensive and sustained one. Medications remain the bedrock of treatment. Medications alone are however not sufficient and patients need much support towards their recovery.

Introduction


The term 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.

More recent contributions have focused on etiology and potential types of schizophrenia:

·         Timothy 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.

·         Peter 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.

·         Robin Murray in England and Daniel Weinberger in the USA have emphasized the notion that schizophrenia is a disorder of faulty brain development.3

·         Nancy 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

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 problem.

Causes of schizophrenia

Ultimately, the exact causes of schizophrenia are not known.6

1. Genetics

Schizophrenia is 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.

Genetic studies 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

Another 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.

People 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.

3. Brain abnormalities and the neurodevelopmental hypothesis

More 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 regions).13

Studies 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.

In 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

It 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

Over 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.

Diagnosis

Diagnostic 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

1. Bipolar Disorder

2. Drug-Induced psychoses

3. Organic related psychoses

(a)     Infections

(b)     Toxins

(c)     Cerebrovascular

(d)     Metabolic

(e)     Endocrine

4. Delusional Disorder

Patients 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

Antipsychotic 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).

Increasingly, 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

Exactly 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.

Second 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.

References

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2.  Stotz-Ingenlath G (2000). "Epistemological aspects of Eugen Bleuler's conception of    schizophrenia in 1911" (PDF). Medicine, Health Care and Philosophy 2000; 3 (2): 153–9.

3. Murray RM, O ‘Callaghan E’, Castle DJ, Lewis SW. A neurodevelopmental approach to the classification of schizophrenia. Schizophrenia Bulletin 1992; 18: 319-32.

4. Andreasen NC. A unitary model of schizophrenia: Bleuler’s fragmented phrene as schizencephaly. Archives of General Psychiatry 1999; 56: 781-7.

5. Thornicroft G, Brohan E, Rose D, et al. Global pattern of experienced and anticipated discrimination against people with schizophrenia: a cross-sectional survey. Lancet 2009; 373: 408-15.

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7.  Lichenstein P, Yip BH, and Bjork C, et al. Common genetic determinants of schizophrenia and Bipolar Mood Disorder in Swedish families: a population based study. Lancet 2009; 373: 234-9.

8. Harrison DJ, Weinberger DR. Schizophrenia genes, gene expression and neuropathology;on the matter of their convergence. Molecular psychiatry 2005; 10: 40-68.

9.  Stefansson H, Rujescu D, Cichon S, et al. Large recurrent microdeletions associated with schizophrenia. Nature 2008; 455: 232-6.

10. Cannon TD, Yolken R, Buka S, Torrey EF. Collaborative study group on the perinatal origins of Severe Psychiatric disorders. Decreased neuroresponse to birth hypoxia in the etiology of schizophrenia. Biological Psychiatry 2008; 64: 797-802.

11. Khashan AS, Abel KM, Mcnamee R, et al. Higher risk of offspring schizophrenia following antenatal exposure to severe adverse life events. Archives of General Psychiatry 2008; 65: 146-52.

12. Kirkbride JB, Boydell J, Ploubidis GB, et al. Testing the association between the incidence  of schizophrenia and social capital in an urban area. Psychological Medicine 2008; 38: 10083-94.

13. Pearlson GD, Calhoun V. Structural and functional MRI in psychiatric disorders. Canadian Journal of Psychiatry 2007; 52: 158-66.

14. Ho BC, Andreasen NC, Dawson JD, Wassink TH. Association between brain derived neurotrophic factor Val66 Met gene polymorphism and progressive volume changes in schizophrenia. American Journal of Psychiatry 2007; 164: 1890-99.

15. Mason P, Riment M, Richman A, et al. Middle ear disease and schizophrenia: case-control study. British Journal of Psychiatry 2008; 193:192-6.

16. Kapur S, Remington G. Dopamine (D2) receptors and their role in atypical antipsychotic action: still necessary and may even be sufficient. Biological Psychiatry 2001; 50: 873-83.

17. Marshall M, Lewis S, Lockwood A, et al. Association between duration of untreated psychosis and outcome in cohorts of first episode patients: a systematic review. Archives of General Psychiatry 2005; 62: 975-83.

18. Mc Gorry PD, Killachey E, Yung A. Early intervention in psychosis: concepts, evidence and future directions. World Psychiatry 2008; 7: 148-56.

19. Tandon R, Nasrallah HA, Keshavan MS. Schizophrenia ‘just the facts’: clinical features and conceptualisation. Schizophrenia 2009; 110: 1-23.

20. Howes OD, McGuire PK, Kapur S. Understanding pathophysiology is crucial in linking clinical staging to targeted therapeutics. World Psychiatry 2008; 7: 162-3.

21. Kapur S, Zipursky R, Jones C, et al. A PET study of quetiapine in schizophrenia: a preliminary finding of an antipsychotic effect with only transiently high dopamine D2 receptor occupancy. Archives of General Psychiatry 2003; 57: 553-9.

22. Carlson MI, Carisson A, Nilsson M. Schizophrenia: from dopamine to glutamate and back. Current Medicinal Chemistry 2004; 11: 267-77.