Schizophrenia

Question 1

Why are males more susceptible to schizophrenia?

Answer 1

• Males tend to have a more severe form of schizophrenia, with brain-imaging studies demonstrated more severe sz-associated brain anomalies. Females also tend towards a better clinical outcome.
• This may be due to sex hormones providing a protective role – declining levels of oestrogen often coincides with worsening of psychotic symptoms.
• Declining levels of oestrogen around menopause may also explain rates of late-onset sz in women. This late onset sz is also associated with more severe clinical presentation.

Question 2

Outline the controversy in diagnosing schizophrenia between DSM-IV and DSM-5.

Answer 2

The DSM-IV ignored cognitive symptoms despite:

• Decreased IQ
• Loss of recall
• Recognition memory
• Working memory
• Impairments in executive control (planning cognitive actions).
• Problems with attention
• Information processing
• Eye movements (altered smooth pursuit).

This is due to the idea that cognitive symptoms do not distinguish schizophrenia from other “boundary” disorders.

Removed subtypes

• Lack of clear distinctions between the various subtypes Issues with DSM-IV Criteria.
• These have poor diagnostic stability over time, people shift between subtypes.
• <5% research looked at subtypes.
• Hierarchical structure for those fitting >1 subtype, this was arbritary, narrow conception for a heterogeneous disorder.
• Subtypes not genetic.
• Can’t measure diagnostic features of subtypes.

Question 3

Outline hallucinations in schizophrenia.

Answer 3

Hallucinations:

• A sensory experience that seems real to the person having it, but occurs in the absence of any external perceptual stimulus.
• They can occur in any modality, but auditory hallucinations are by far the most common- being found in 75% of schizophrenic patients sampled (compared to 39% visual, and 1-7% tactile, olfactory, and gustatory).
• Patients can become emotionally involved in their hallucinations, often incorporating them into their delusions.
• People who consider themselves socially inferior perceive their voices to be more powerful and compelling than they are, and so behave accordingly (Paulik, 2011).
• Voices are often of people they know, but may be from God or the Devil.
• Most patients report hearing more than one voice, and that their hallucinations are worse when they’re alone.
• Most commonly, hallucinated voices utter vulgarities and expletives, were critical, bossy, or abusive, while others were pleasant and supportive.

Question 4

Outline delusions in schizophrenia.

Answer 4

Delusion:

• An erroneous belief that is fixed and firmly held despite clear contradictory evidence.
• People with delusions believe things that others who share their social, religious, and cultural backgrounds do not believe.
• 90% of schizophrenics experience delusions at some point.
• Certain types of delusions are more characteristic than others:
  
  • Beliefs that their thoughts, feelings, or actions are being externally controlled.
  • Thought broadcasting
  • Thought insertion
  • Thought withdrawal.
  • Delusions of reference (some neutral environment such as a TV program is believed to have a special person or meaning).
  • Delusions of bodily changes (e.g. removal of organs).

Question 5

Outline disorganised speech and behaviour in schizophrenia.

Answer 5

• Disorganised speech is the external manifestation of a disorder in thought form.
  
  • Failure to make sense (despite conforming to semantic and syntactic rules) is not attributable to low intelligence, poor education, or cultural deprivation.
  • This process has been referred to as “cognitive slippage”, “derailment”, “loosening” of associations, or even “incoherence”.
• Formal thought disorder refers to problems in the way that disorganised thought is expressed in disorganised speech.
• Disorganised behaviour manifests in many way:
  
  • Goal-directed behaviour is almost universally disrupted, and is impaired in routine daily functioning. For example, they may not maintain minimal standards of personal hygiene.
  • May be attributable to impairments in the PFC, disrupting executive functioning.
• Catatonia: Virtual absence of all movement and speech in what is called a catatonic stupor. May otherwise hold an unusual posture for an extended period of time without any seeming discomfort.

Question 6

Outline negative symptoms in sz.

Answer 6

• Negative symptoms reflect an absence or deficit of behaviours normally present, such as flat affect, alogia, avoliton, and anhedonia.
• In the case of flattened affect, while sz patients may not look as if they are experiencing as much emotion as controls when watching very positive or very negative film clips, as observed by researchers, they tend to report experiencing just as much emotion (Kring & Neale, 1996).

Question 7

Where do sz hallucinations stem from?

Answer 7

• Neuroimaging studies found that auditory hallucinations seem to stem from Broca’s area, rather than Wernicke’s area or the temporal lobe. T
• his pattern of activity is also seen when healthy volunteers are asked to imagine another person talking to them.
• This suggests that auditory hallucinations occur when patients misinterpret their own self-generated and verbally mediated thoughts.

Question 8

Outline and evaluate what twin studies have shown about sz..

Answer 8

• Being a twin does not increase one’s risk of developing sz, but there is a higher concordance for sz among MZ twins (28%) than among DZ twins (6%; Torrey et al. 1994). This suggests that a reduction in shared genes from 100% to 50% reduces sz risk by nearly 80%. MZ concordance has never been close to 100%. Two conclusions can be drawn from this:
  
  1. Genes undoubtedly play a role in sz.
  2. Genes themselves are not the whole story.
• Fischer (1971) reasoned that genetic influences, if present, would be just as likely to show up in the offspring of the twins without sz in discordant pairs, as they would be to show up in the offspring of twins with sz.
  
  • This is indeed the case. Gottesman and Bertelsan (1989) reported an age-corrected incidence rate for sz of 17.4% for the offspring of MZ twins without schizophrenia, which was not significantly different from those with schizophrenia.
  • Important to bear in mind that around 2/3 MZ embryos are monochorionic. 1/3 MZ embryos and all DZ embryos are dichorionic.
  • As a result, because most MZ twins and DZ twins have differing prenatal environments, MZ concordance rates are likely to be vastly overestimated. Monochorionic MZ twins are much more likely to share infections, and are much more likely to develop sz than DZ twins.

Question 9

Outline and evaluate what adoption studies have shown about sz.

Answer 9

Twin studies assume that the MZ twin environment is equally as similar to the environment of DZ twins. However, it is reasonable to expect that the MZ twin environment will be more similar, and so to the extent that this is true, twin studies will overestimate concordance rates.

Adoption studies can overcome this limitation.

• Heston (1966) followed up 47 children born to hospitalised sz mothers who were fostered within 72 hours of birth. 16.6% of these children were later diagnosed with sz, compared to none of the 50 control children (residents of the same foster home). They were also more likely to be diagnosed as mentally retarded, neurotic, or psychopathic, had more criminal activities and spent more time in criminal institutions.
  
  • This suggests that a genetic liability by the mothers was not specific to sz. HOWEVER, information about the fathers of the children was not provided.

Question 10

What has molecular genetics shown about schizophrenia?

Answer 10

• Likely that hundreds of genes could be implicated for sz.
• Researchers use DNA markers to learn where aberrant genes lie. DNA markers are known locations of some important genes associated with observable traits (e.g. colour blindness, blood group, human leukocyte antigen). Researchers can see whether schizophrenia co-occurs with any known DNA marker traits- this is linkage analysis.
  
  • One example of a candidate gene is the COMT gene. This is located on no. 22 and is involved in dopamine metabolism. Children who have velocardiofacial syndrome, which involves deletion of material from no. 22 are at high risk of sz through adolescence. Furthermore, a particular variant of the COMT gene is implicated in increased likelihood of developing cannabis-induced psychosis.
  • Other potential candidate genes are neuregulin 1, the dysbindin gene, the DISC1 B (Disrupted in Schizophrenia) gene, and several dopamine receptor genes. Genetic findings are frustratingly non-replicable and inconclusive.

Question 11

Why should we study endophenotypes in sz?

Answer 11

• Instead of focusing on less complex and more homogenous phenotypes (e.g. symptom clusters), researchers are beginning to explore endophenotypes- discrete, stable, and measurable traits thought to be under genetic control.
• Endophenotypic risk markers for sz include magical ideation, perceptual aberrations, and abnormal performance on measures of cognitive functioning. By studying these traits as opposed to the disorder of sz itself, research can be speeded up.

Question 12

Outline prenatal exposure risk factors in sz (viral infection, Rh pregnancy and birth complications, early nutritional deficiency, maternal stress).

Answer 12

Viral Infection

• In 1957 there was a major influenza epidemic in Finland.
• Elevated rates of sz were found in children born to mothers who were in their 2nd trimester at the time of the epidemic.
• Risk of sz seems to be highest in mothers who are infected with flu in the 4th-7th months of gestation.
  
  • Small effect size.
• One possible explanation is that mother’s antibodies somehow disrupt foetal neurodevelopment as they cross the placenta. O
• ther viruses such as rubella and toxoplasmosis have been implicated.

Rhesus Incompatibility

• Rh incompatibility seems to be associated with increased risk for sz. Hollister, Laing, and Mednick (1996) found a 2.1% rate of schizophrenia in males who were Rh incompatible with their mothers, compared to 0.8% who were compatible.
• A possibility is that the mechanism involves hypoxia, increasing risk of brain abnormalities and birth complications.

Pregnancy and Birth Complications

• Patients with sz are much more likely to have been born following a pregnancy/delivery that was complicated in some way, for example, breech delivery, prolonged labour, wrapped umbilical cord, will affect the oxygen supply of the newborn.

Early Nutritional Deficiency

• The Hungervinter occurred at the end of WWII in the Netherlands. The population was severely malnourished, with many dying of starvation.
  
  • Fertility levels and birth rate dropped precipitously.
  • The children who were born during this time were at a 2x increase of sz.
  • Early prenatal nutritional deficiency appears to have been the cause- it is unclear whether this was general or specific to nutrients like folate or iron.

Maternal Stress

• The death of a close relative during the 1st trimester was associated with a 67% increase in the risk of sz in the child (Khashan et al. 2008).
• May be that stress hormones passed to the foetus may negatively affect brain development, but this is not well understood.

Question 13

Outline the seasonality effect in sz.

Answer 13

• More schizophrenic births in winter effect, small effect but robust (birth dates of siblings show this is not a bias to procreate in summer).
• Seasonal Perinatal Risk Factors
  
  • Link with winter births and viral events.
  • Stress in pregnancy
    
    • 67% increased risk of schizophrenia in offspring exposed to more stress in utero (Khashan et al, 2008)
  • Risk signs include low birth weight, pre-eclampsia (hypertension in late stages of pregnancy).
  • Perinatal complications
    
    • Cannon et al (1993;2002) 3 classes of complications associated with increased risk of schizophrenia (but some evidence that only when a parent has schizophrenia):
      
      1. Complications of pregnancy.
      2. Abnormal foetal growth.
      3. Complications of delivery.
    • Perinatal effect remains after socioeconomic status is accounted for.
    • Birth complications more common in schizophrenic member of discordant twin.
• Dutch famine study.

Question 14

Outline and evaluate the neurodevelopmental perspective of sz (prodromal stage).

Answer 14

• Current belief is that sz is an illness that develops early, but symptoms do not become apparent until early adulthood- when the brain finally fully matures.
• Some genes implicated in schizophrenia are known to play a role in brain development and neural connections.
• Cell migration may be impaired, resulting in abnormal internal connectivity in the brain. This occurs in the second trimester (when maternal influenza is most devastating).
• There are even early indications of schizophrenia in children. Family home movies made during the childhoods of 32 people who eventually developed sz. Trained observers made “blind” ratings of certain dimensions such as emotion and facial expressions, motor skills, and neuromotor abnormalities of these children and their healthy outcome sibling in the same clips. Pre-schizophrenic children had significantly more motor abnormalities (especially hand movements), and showed more negative facial emotion and less positive. In some children, signs were seen as early as age 2.
• Other evidence of prodromal signs of schizophrenia has come through prospective research (both with high genetic risk and normal risk children).
  
  • Erlenmeyer-Kimling et al (1998) reported that of an initial group of 51 high-risk children, 10 developed sz or sz-like psychosis as adults. Of these, 80% showed unusual motor behaviour when they were between 7-12 years old.
  • Mittal et al. (2008) found that high-risk adolescents showed more motor abnormalities (facial tics, blinking, tongue thrust) than either nonclinical controls or adolescents with personality or behavioural problems. Motor abnormalities is how schizotypal brain abnormalities may first manifest.

Question 15

What do szs show in neuropsychological measures. Evaluate these measures.

Answer 15

• Szs perform much worse on neuropsychological tests than do controls, implicating a wide range of brain regions. This is not due to the effects of extended hospitalisation/medication (recent patients tested perform the same).
• Szs have a deficit in reaction time.
• They also show deficits on the Continuous Performance Task, demonstrating impairments in attention.
• There are also problems with working memory (Barch, 2005), displaying less prefrontal activity than healthy controls.
• 54-86% of szs show eye-tracking dysfunction, and are deficient in their ability to smoothly pursue a moving target such as a pendulum (Cornblatt et al. 2008). 50% of first degree relatives of szs show this deficiency too.
• The psychophysiological measure P50 (Heinrichs, 2001) presents two clicks heard in close succession. Normally, the brain will produce a positive electrical response 50ms after each click. In normal controls, the response to the second click is dampened, or “gated” as the brain habituates. Many patients with schizophrenia, however, display poor P50 suppression. First degree relatives of szs are more likely to have this as well. This may be due to compromise in the hippocampus (one of the areas most susceptible to early hypoxic damage).
• Some szs exhibit hypofrontality when involved in tasks like the WCST. In others, hyperactivity of the frontal lobe is displayed- showing they have to work harder to be successful at the WCST. In both circumstances, the brain is not functioning optimally. Again, neither unique nor universal. Most important problem is the way activity in different brain regions is coordinated. Schizophrenics appear to have difficulty disengaging from the “default mode network” (Guerrero-Pedrazza et al. 2011).

Question 16

Outline and evaluate the neuroanatomical hallmarks of sz.

Answer 16

Cytoarchitecture

• Disruptions in cell migration means disruption of the brain’s cytoarchitecture.
• Appears to be an increase in neuronal density in certain areas of the brain in szs, as well as abnormalities in cell distribution in layers of the cortex and hippocampus – downward-shift phenomenon.
• Also evidence that szs are missing “inhibitory interneurons” (Benes & Berretta, 2001) which are responsible for regulating the excitability of other neurones.

Question 17

Outline and evaluate the dopamine hypothesis of sz.

Answer 17

• The dopamine hypothesis is the most prominent theory of schizophrenia development, and was derived from three compelling observations:
  
  1. Chlorpromazine, a dopamine antagonist, seems to help alleviate positive symptoms of schizophrenia.
  2. High doses of amphetamine, a dopamine agonist, induce psychotic symptoms such as hallucinations and paranoia.
  3. Clinical observations of L-Dopa, a drug used to increase dopamine levels in Parkinson’s disease sufferers, have shown that psychotic symptoms are a significant complication of the treatment (Butcher, Hooley, & Mineka, 2014).
• Fifty years after the first observation however, pharmacological treatment of schizophrenia remains virtually unchanged. This is despite dopamine antagonists having little to no effect on negative symptoms and cognitive deficits, with positive symptoms persisting in a significant number of patients (Moghaddam & Javitt, 2012).
• The only way to measure total dopamine content of the brain is through post-mortem studies (e.g. Cross, Crow, & Owen, 1981).
  
  • While these studies have found more D2 receptors in the brains of people with schizophrenia than those of controls, the former have been likely subject to a prolonged period of antipsychotic treatment which may have altered the distribution of dopamine receptors.
  • Indeed, animal research has suggested that neuroleptic drugs increase the incidence of dopamine receptors after a few days (Muller & Seeman, 1978).
• However, evidence does suggest elevated levels of D2 receptors in healthy co-twins of patients with schizophrenia (Hirvonen et al. 2005). The dopamine hypothesis has numerous problems, and it is currently now believed to work in conjunction with abnormalities in other neurotransmitter systems, in particular the glutamatergic system.

Question 18

How may the glutamate hypothesis overcome the limitations of dopamine hypothesis?

Answer 18

• Clinical, neuropathological, and genetic findings have implicated a hypofunction of glutamatergic signalling in people with schizophrenia.
  
  • Evidence mostly comes from phencylidine (PCP) and ketamine, which are known to block glutamate receptors and also induce both positive and negative symptoms of schizophrenia (Lahti, Weiler, Tamara, Parwani, & Tamminga, 2001).
  • Interestingly, ketamine does not cause these problems when administered to children, which suggests that age and brain maturity determines whether ketamine causes psychosis.
• The glutamate hypothesis does not oppose the dopamine hypothesis but instead compliments it. Dopamine acts to inhibit the release of glutamate, and so a hyperactive dopaminergic system could result in excessive inhibition of glutamate (Butcher, Hooley, & Mineka, 2014).

Question 19

-> Outline psychosocial and cultural factors in sz.

Answer 19

Do Bad Families Cause Schizophrenia?

• Used to be thought to be the case.
• Double-bind theory used to be influential, but now it is believed that disturbances and conflict in families may well be caused by having a schizophrenic person in the family.
  
  • High communication deviance may actually reflect genetic susceptibility to schizophrenia on the relative’s part.
• As learned from the Finnish Adoption Study, however, adverse family environments and communication devices are unlikely to have a pathological consequence on a child not at genetic risk for schizophrenia.

Families and Relapse

• Highly emotional parental/spouse environments may cause relapse. Risk is higher than patients who left hospital to live alone or with siblings.
• Brown (1985) developed the theory of expressed emotion- a measure of the family environment based on how a family member speaks about the patient during a private interview along three dimensions: criticism, hostility, and emotional over-involvement.
• Most important is criticism, which reflect dislike or disapproval of the patient.
• EE predicts relapse regardless of whether the patients studied have been ill for a short, medium, or long period of time.
• Particularly strong predictor for chronically ill patients.
• Expressed emotion is often accompanied by well-meaning, but intrusive and controlling attempts to “help” the patient, which triggers cortisol release, increasing the likelihood of relapse.
  
  • When a patient says something strange, a high-EE relative is likely to criticise them.
  • Interestingly, this is often followed by another strange remark from the patient- unusual thinking occurred immediately after criticism (Rosenfarb et al. 1995).

Urban Living

• Appears to increase a person’s risk of developing schizophrenia. Immigration Stress and social adversity from immigration appears to be a risk factor for schizophrenia.
• Those with darker skin have a much higher risk of developing schizophrenia than those with lighter skin. This may reflect increased paranoia and suspicion as a result of more discrimination.

Question 20

Outline clinical outcomes of sz.

Answer 20

• 15-25 years after developing schizophrenia, around 38% of patients have a generally favourable outcome and can be thought of as being recovered (Harrison et al. 2001), often with the help of therapy and medications.
• 12% need long-term institutionalisation.
• ~1/3 of patients show continued signs of illness, usually with prominent negative symptoms.
• When more stringent criteria of functioning is used, full rates of recovery are only ~14%.
• Patients in less industrialised countries appear to do better overall than patients in industrialised nations (maybe less EE?).

Question 21

Outline and evaluate first generation antipsychotics in treating sz.

Answer 21

• Antipsychotics seem effective in helping reduce the positive symptoms of schizophrenia by blocking D2 receptors (they are dopamine agonists).
• Some clinical change can be seen in the first 24 hours of treatment.
• Common side effects include drowsiness, dry mouth, and weight gain.
• Many patients also experience extrapyramidal side effects. These are involuntary movement abnormalities (muscle spasms, rigidity, shaking) that resemble Parkinson’s disease.

Question 22

Outline and evaluate second generation antipsychotics in treating sz.

Answer 22

• Clozapine was introduced in the US in 1989 and is now used widely.
• Second generation antipsychotics cause fewer extrapyramidal symptoms than first generation antipsychotics, but they are no more effect with the exception of clozapine, which may be more helpful for treatment refractory patients.
• Despite being less likely to cause movement problems, drowsiness and considerable weight gain are very common.
• Diabetes is also a serious concern.
• Rarely, clozapine can cause agranulocytosis- a life-threatening drop in white blood cells.

Question 23

fOutline and evaluate psychosocial approaches to treating sz.

Answer 23

Family Therapy

• Idea is to reduce relapse in schizophrenia by reducing levels of EE in the patient-relative relationship. This practically involves educating patients and families about schizophrenia, help improve their coping and problem-solving skills, and to enhance communication skills, especially in terms of clarity.
• Patients tend to do clinically better and relapse rates are reduced.

Case Management

• Case managers act as a broker to help the patient to obtain service providers, such as treatment, employment, housing, etc.
• Assertive community treatment programs reduce the time patients spend in the hospital and increase stability of housing arrangements, therefore they are cost effective.

Social-Skills Training

• Aimed at increasing the functional outcome (rather than the clinical outcome) of patients. Szs often have poor interpersonal skills, and so this training is intended to help the patient acquire the skills they need to function better day-to-day.
• These may include employment skills, relationship skills, self-care skills, and skills in managing medication and symptoms.
• Social routines are broken down into smaller more manageable skills, for example, in conversation some components may include learning to make eye contact, speaking at a normal volume, taking turns, etc.
• Patients get corrective feedback and engage in roleplaying to practise in natural settings.
• Recent findings are positive and seem to be maintained over time, reducing relapse likelihood.

Cognitive Remediation

• Researchers try and help sufferers improve some of their neurocognitive deficits, in the hope that this will translate into better overall functioning (e.g. conversational skills, self-scare, job-skills, etc.).
• Overall, findings are optimistic even in patients that have been ill for many years.
• Cognitive remediation works best when added to other rehabilitation strategies in patients who are clinically stable (Wykes et al. 2011).

CBT

• The goal of CBT in schizophrenia is to decrease the intensity of positive symptoms, reduce relapse, and decrease social disability.
• The therapist and patient explore the subjective nature of the patient’s delusions and hallucinations, examine evidence for and against their veracity or veridicality, and reality test their beliefs.
• Only performs well for some subgroups.

Question 24

How does the quality of the adoptive family affect development of sz?

Answer 24

• The Finnish Adoptive Study of Schizophrenia followed up the adopted-away children of all women in Finland hospitalised for schizophrenia between 1960 and 1979.
• The functioning of these index children were compared with the functioning of a control sample of adoptees whose mothers were healthy.
• The researchers looked at the family environment.
  
  • One facet of this was communication deviance- a measure of how understandable and “easy to follow” the speech of the family member’s is.
  • The combination of genetic risk and high communication deviance in the adopted families was problematic in that they were highly likely to show high levels of thought disorder.
  • Those with no genetic risk showed no though disorder, regardless of communication deviance levels.
  • Most surprising were the results for high genetic risk, low communication deviance groups who were healthier at follow-up than any of the other 3 groups!
• Strong evidence of gene-environment interaction found in other interview studies measuring degree of adversity in the family environment.
• Only those raised in dysfunctional families and had high genetic risk of sz went on to develop sz-type disorders.