Psychobiology of Mental Illness

INTRO

 

Psychobiology: studying the biological basis of behaviour and mental phenomena; the effect of biological influences on psychological functioning

Psychopathology: the scientific study of mental disorders, including efforts to understand their genetic, biological, psychological, and social causes

 


 

SCHIZOPHRENIA

Psychiatric disorders: disorders of psychological function sufficiently severe to require treatment

DSM-IV-TR: diagnostic and statistical manual of the American Psychiatric Association

Schizophrenia: literal – ‘the splitting of psychic functions’

 

WHAT IS SCHIZOPHRENIA?

Positive symptoms: delusions, hallucinations, odd behaviour, incoherent speech, inappropriate affect

Negative symptoms: affective flattening (emotional expression), alogia (speech), avolition, anhedonia (pleasure)

 

CAUSAL FACTORS 

Genetic factors

– 10% chance of close biological relative having schiz, even if adopted after birth

– 45% concordance in identical twins over fraternal (10%)

– 40% to 60% chance if both child’s parents affected

– Tandon et al (2008) – genetic factors account for 80% of its appearance

– no risk increase with adopted parents, but increase with biological parents

– identical twin parents: one with schiz and one not – chance of schiz in their kids same

– early experiences could alter neurodevelopment > schiz in those with genetic predisposition

– e.g. birth complications, early infections, toxins, stress, famine, traumatic injury

 

ARTICLE: Jablensky (2000) – “Epidemiology of Schiz: the global burden of disease & disability” (review article, genetic factors)

– occurs universally with similar prevalence, characteristics, age & gender patterns

– genetic, neurodevelopmental & env contributions to cause are unknown

– not much support for a single schiz gene: multiple involved

– 50% MZ concordance suggest predisposing genes not enough: environment

 

Dr Oliver Howes (2015) – BBC News (genetic factors)

Microglia in an overactive immune system >> schizophrenia

– microglia weed out infection & prune unwanted connections bet. brain cells

– schizophrenia & at risk had higher microglia activity levels

– microglia are cutting wrong connections >> incorrect wiring

 


 

ENVIRONMENTAL & DEVELOPMENTAL FACTORS (not psychobiological accounts)

Tienari et al (1987) – studied children of schiz mothers adopted away early in life

children adopted by well-adjusted families least likely to dev schiz

 

Article: Jablensky (2000) – “Epidemiology of Schiz: the global burden of disease & disability” (review article, environmental factors)

– maternal influenza cause unproven

– brain damage & CNS infection around birth a significant factor

– lower IQ means higher risk

– positive relationship with epilepsy

– very high rates in 2nd generation Afro-Caribbeans: racism, limited opportunities

– size of urban area linked

– spring/ winter season of birth link suggested

– decline in prevalence suggested but not proven

– no major environmental factor has yet been found

 


 

DOPAMINE HYPOTHESIS (psychobiological account)

– in 1950s was found that chlorpromazine & reserpine had anti-schiz fx

– they also induced symptoms similar to Parkinson’s (tremors at rest, rigidity)

– in 1960 found striatums of Parkinsons patients had DA depletion

 

Carlson & Lindqvist (1963) – chlorpromazine was DA receptor blocker

– high levels of activity at DA receptors > schiz (not high DA)

 

Davis (1974) – injected amphetamine-like drug into schiz patients in remission

– within 1 minute went from “mild schiz to florid schiz”

 

Snyder (1978) – potency of anti-schiz drugs related to strength of D2 receptor binding

 

LIMITATIONS OF DOPAMINE THEORY

1) Other receptors than D2 are involved

Gonzalez-Maeso & Sealfon (2009)

– LSD & PCP > schiz symptoms via serotonergic & glutaminergic neurotransmitters

– atypical neuroleptics (non D2) e.g. clozapine has affinity for D1, D4 & serotonin receptors but only slight for D2

 

2) Neuroleptic therapy takes weeks to affect schiz

– neuroleptics block activity at D2 receptors in hours but schiz effect takes weeks

– could be that D2 blocking triggers another change that’s the key factor

 

3) Schizophenics have widespread brain damage

DA hypothesis gives no reason for the widespread brain damage

Kubicki et al (2007) – reduced brain damage in 50 regions

Honea et al (2005) – brain damage in grey and white matter esp. temp lobes

Walker et al (2004) – widespread neuron loss & abnormalities in neuron structure & circuits

Egan & Weinberger (1997) – no evidence of specific structural damage to dopaminergic circuits

Vita et al (2006) :

1) extensive brain damage on first scan

2) further scans show brain damage continues to develop

3) damage to different areas at different rates

 

Karlsgodt et al 2010 (support for biological basis – neurodevelopmental account)

– schiz caused by disrupted neural connectivity, caused by genetic & environmental risk factors at birth & adolescence

– suggests imaging tech can show us who’s at risk and who will develop disease

– suggests a new biological basis

 

4) Neuroleptics are only marginally effective

Adams et al (2005) – vs placebo clear beneficial effects only at 6 months

– only 1 in 7 of these helped substantially

 

Murphy et al (2006) – neuroleptics act only on some positive symptoms

 


 

ARTICLE: Grace (2010) – “Ventral Hippocampus, Interneurons & Schizophrenia”

  • a new DA hypothesis
  • little e.g. postmortem evidence that root of schiz are in doperminergic neurons
  • hyperactivity in hippocampus causes disruption in DA system function
  • so normalizing hippocampus function prob more effective than DA receptor blocking

 

These new hypotheses can better align several lines of evidence e.g. DA + other NTs + other regions + env

 


 

ARTICLE: Moncrieff & Cohen (2009) – “How do psychiatric drugs work”

– question assumption that drugs work on the neurochemical causes of a disorder

– rather drugs simply cause a drug induced state

Disease/medical centered model: biological causes; psychiatric drugs correct an abnormal brain state

Drug centered model: drugs put a person in a different mental & physical state

– traditional view that drugs act on the cause and other effects are side effects

– Moncrieff argues drugs are psychoactive, producing general not specific therapeutic fx

– psychoactive effects of drugs (motor slowing, sedation etc) could be effective in lots of disorders (e.g. sleep disturbance or arousal)

– suggest disorder specific drugs are no more effective than other psychoactive drugs e.g. opium

– drugs which aren’t antidepressants (e.g. benzodiazepines) have similar effects to antidepressants (special status of antidepressants not justified)

 

DA HYPOTHESIS

– no strong evidence that DA abnormality itself causes psychosis instead of DA related activity e.g. arousal or stress

– some effective antipsychotic drugs (e.g. clozapine) have weak action on DA receptors

– monoamine hypothesis the same: no evidence of NA/5-HT deficiency in depressed people

– antidepressants are claimed to work by correcting lack of these (NA/5-HT)

 

CONCLUSION

– drugs shouldn’t be said to target specific diseases because of lack of evidence

– they should be said to produce certain states and patients can decide whether good/bad

– it’s difference bet. “this drug targets bio cause of depression” and “this drug produces an altered state”

– researchers must detail effects of drugs on thought, emotion and body

 


 

PROGNOSIS & TREATMENT

ARTICLE: Jobe & Harrow – “Schizophrenia course, long term outcome, recovery & prognosis”

  • subgroup of 20% to 30% of patients who recover and taken off antipsychotics
  • many function for a number of years without treatment
  • few are on a constant downhill course
  • studies show poorer outcome vs. patients with other disorders
  • OC: if schiz understood outcomes would be better
  • reocurrence related to vulnerability + risk factors (e.g. stress, personality, cog traits)
  • antipsychotics partly helped better outcome during acute phase & after

 

ARTICLE: Jablensky (2000) – “Epidemiology of Schizophrenia: the global burden of disease and disability”

  • better outcomes in developing countries

 



 

DEPRESSION

Anhedonia: loss of capacity to experience pleasure

Clinical depression: symptoms for > 2 weeks: sleepless, suicidal, suicidal, unsocial, excess/insufficient diet, neglect hygiene

Mood/ affective disorder: disturbances in mood or emotion

Mania: overconfidence, impulsivity, distraction, high energy

Bipolar affective disorder: periods of mania & depression

Unipolar affective disorder: depression only

Reactive depression: onset due to event

Endogenous depression: with no apparent cause

 

GENETIC CAUSES 

– 60% concordance rate for identical twins (15% frat), even where raised apart

– affected twins tend to suffer same type of disorder

– not good evidence linking stress to affective disorders

 

NEUROCHEMICAL CAUSES (psychobiologial account)

– drug treatments give clues on biochemical causes

– antidepressants e.g. imipramine stimulate synapses using NE and 5-HT

– reserpine can cause depression by blocking NE and 5-HT

– so depression caused by depletion in monoamines: DA, NE or 5-HT

– serotonin hypothesis: blocking 5-HT reuptake more effective than blocking NE reuptake

Sancora et al (2002) – drugs that increase 5-HT increases GABA

– roles of GABA classes a & b in depression aren’t clear

 

NEUROPATHOLOGICAL CAUSES (psychobiological account)

Drevets et al (1997)

– activity in PFC near top of corpus callosum reduced and area was smaller

– also reduction in cell density and glial cells

– these cells carry neurotransmitter receptors and help transport neurotransmitters so…

 

Swabb et al (2005)

– dysfunction in hypothalamus >> increased cortisol

– levels are higher in depressed vs controls

 

GEOGRAPHY (alternative to psychobiological account: environmental account)

Sundqvist et al (2004)

– patients in most densely populated areas 12-20% more likely risk of developing depression

– survey was entire Swedish population aged 25-64

– could be due to stressful living and little support

 


 

ANTIDEPRESSANT DRUGS (cause & account – drugs do xyz so Neurotransmitters are part of the cause)

Monoamine Oxidase Inhibitors (e.g. iproniazid 1957)

– monoamine agonist (NE & serotonin) against MAO enzyme that breaks them down

– monoamine neurotransmitters in cytoplasm (cellular fluid) of neuron

– takes 1-3 weeks to have effect

 

Tricyclic Antidepressants (TCA e.g. imipramine)

– ‘tricyclic’ antidepressants because of 3 ring chemical structure; were earliest antidepressants

– reuptake blockers of norepinephrine & serotonin so increasing their levels in brain

– biology of depression not understood; we don’t know how neurotransmitters>> depression

– believe it’s deficiency of NA & 5-HT; drugs seem to slow down reuptake

Hughes & Pierattini (1992) – works for 60-80% extreme depression

 

Selective monoamine reuptake inhibitors (SSRIs e.g. prozac 1980s)

– serotonin reuptake agonists (SSRI serotonin specific)

– claimed to act against range of psych disorders apart from depression

– also SNRIs (selective norepinephrine reuptake inhibitors) as effective as SSRIs

Barbui et al: SSRI no clinical advantage over placebo in minor depression

 

DRUG EFFECTIVENESS (against drug based theories)

Kirsch et al (2008)

4 most commonly prescribed antidepressants – placebos were 82% as effective as drugs

(especially for mild to moderate depression)

BUT:

Paris (2011)

– believes that Kirsch and Moncreiff have overstated the ineffectiveness of drugs

– for severe depression placebo effect is less and drug effectiveness greater

 

Hensley et al (2004) – CBT can be even more effective than antidepressants

 


 

BRAIN PATHOLOGY (psychobiological account)

– inconsistent results regarding reduction in brain size & various parts

Gotlib & Hamilton (2008) + many others: abnormal cell loss in amygdala & anterior cingulate cortex

 

THEORIES OF DEPRESSION (psychobiological accounts)

Monoamine theory of depression (psychobio account)

– popular antidepressants are all agonists of serotonin, norepinephrine or both

– Nemeroff (1998) – up-regulation in brains of dead untreated depressed people

when insufficient neurotransmitter released, receptors for NT increase

– BUT support for theory weak: few patients benefit from antidepressants

 

Diathesis-stress model of depression (part psychobio account)

Pariante & Lightman (2008) – people inherit a diathesis (genetic tendency) that’s permanently sensitized if they experience stress in early life

– BUT little evidence of excessive early stress in majority of depressed patients

 

Beck & Kovacs 1978 (not psychobiological account)

  • people see events through a schema – stored collection of knowledge
  • If schema is depressive triggers series of negative thoughts & experience
  • If no triggers then they will think & behave like a non-depressive

 

Brain stimulation (psychobio account)

Electrical pulses to anterior cingulate gyrus has given promising results, but more research required

 


 

Conclusion – this document in a sentence:

there appears to be an inherited biological basis to mental illness. Drugs appear to alleviate acute symptoms of mental illness but to suggest that drug action tells us the cause of mental illness seems doubtful. DA & Monoamine theories have been questioned and other explanations have been put forward.