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Psychiatric disorders

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Disorders of Mind & Brain

Mind and brain are two sides of one coin; disorders of the mind are disorders of the brain.

Particular clusters of symptoms (syndromes) tend to occur together in various different mental illnesses

The ways in which symptoms cluster together tells us something about the structure of the human mind and brain

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Anatomy of psychiatric disorders

Contemporary psychiatry implicates neurotransmitters rather than anatomy.– Schizophrenia :: dopamine– Depression :: serotonin

To some degree, this may reflect the popular treatments – neurotransmitters specific to brain regions.

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Major symptom clusters

Reality distortionDisorganizationPsychomotor poverty Psychomotor excitationDepression EuphoriaAnxiety

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Reality distortion

Mismatch between representation of reality in individual’s mind and representation supported by objective evidence

Hallucinations and delusions– Tend to occur together– Tend to respond similarly to dopamine

blocking medication

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Hallucination: perception with quality of a sensory perception but nor derived form stimulation of a sense organ– Individual usually falsely attributes perception’s

origin to external world

Delusion: fixed belief derived by erroneous inference or unjustified assumption that cannot be accounted for by culture or religion

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Delusions

Delusions usually false but the key issue is lack of rational grounds and fixity.

Ability to engage in logical deduction about other issues is usually intact; certain ideas seem exempted from the need for logic.

Non-psychotic distortions of reality (eg in OCD or in non-psychotic depression) reflect biased thinking but are less resistant to debate

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Psychotic Reality Distortion

Can occur in schizophrenia, mania, psychotic depression, brain injury or degeneration

Themes: persecution; alien control, religion, grandiosity, guilt

Influenced by culture, but some themes are common across cultures

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Reality distortion in schizophrenia

Characteristic forms (but not present in every case)– Delusions of alien influence over thought,

volition, action, affect, bodily function –characteristic

– Third person auditory hallucinations

Less specific but common forms:– Persecutory delusions (52%), delusions of

reference (50%)– Second person auditory hallucinations

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Affective psychosis

Mood disorder with psychotic features is diagnosed if psychotic illness is dominated by mood symptoms unless there is reality distortion without substantial mood symptoms for at least two weeks

Delusions and hallucinations are usually mood congruent (eg guilt, worthlessness, critical voices with depressed mood; grandiose delusions and self-reinforcing halluciations in mania)

Reality distortion shows similar response to antipsychotic medication irrespective of diagnosis

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11Neuropsychological correlates of reality distortion

Reality Distortion can occur in absence of general defect in reasoning.

Defective internal monitoring of self-generated mental activity (Frith & Done 1989; Mlakar et al, 1994)

Jumping to conclusions – the bead test (Huq et al, 1988)

Patients with persecutory delusions tend to attribute negative outcomes to external causes (Bentall, 1994)

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12Regional cerebral activity and reality distortion

Early SPECT studies reported over-activity in medial temporal lobe (eg Musalek et al 1989)

More recent PET studies demonstrate overactivity in left parahippocamapl gyrus and hippocampus (Liddle et al 1992; Silbwersweig et al, 1995)

Liddle et al, 1992

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13Neurochemistry and pharmacology of reality distortion

Antipsychotic drugs that block dopamine D2 receptors decrease reality distortion

Dopamine agonists (eg amphetamine, cocaine) exacerbate delusions and hallucinations

Amphetamine produces greater increase in intra-synaptc dopamine in schizophrenia than in healthy individuals (Laruelle et al 1996)

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Pharmacology of reality distortion

Serotonin = 5-hydroxytryptamine, or 5-HT

5HT2 receptor agonists such as LSD (which reduce 5HT signalling via autoreceptors) are hallucinogenic

Glutamatergic blockers (eg ketamine) can also produce reality distortion

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Hypothesis for generation of reality distortion

Episodic memories rely on context for evaluation and validation; semantic memories (eg Paris is capital of France) do not require contextual validation

Neural circuits in hippocampus generate a ‘validation’ signal when a mental event (eg an episodic memory) fits its context promoting consolidation of the memory

Aberrant hippocampal firing might reinforce incidental thoughts irrespective of context and allow consolidation without need of contextual validation – delusion formation

Internal speech might be processed without context thereby becoming detached from internal source- hallucinations

Dopamine hyperactivity might reinforce the effect of hippocampal overactivity via the striato-thalamo-cortical feed back loops which mediates the hippocampal signal (This might be blocked by antipsychotic drugs)

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Disorganization syndrome

Disjointed thought, emotion, behaviour Formal thought disorder, inappropriate affect,

bizarre behaviour Speech shows ‘looseness of associations’,

‘derailment’, replies can be tangential or incoherent

Occurs in schizophrenia (a core feature); mania (less commonly); frontal lobe damage.

Severity of disorganization is strong predictor of poor occupational and social function

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17Neuropsychological correlates of disorganization

Core executive processes, especially the selection between competing mental events. Poor Stroop performance (Liddle & Morris, 1991);Errors of commission in CPT (Frith et al 1992)

Abnormal spreading of semantic and phonological associations (Spitzer et al 1994)

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18Regional cerebral activity and disorganization

Liddle et al, 1992

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19Regional cerebral activity and disorganization

PET study (Liddle et al 1992): – increased activity in medial frontal cortex/anterior

cingulate & thalamus; – decreased activity in ventral prefrontal cortex, insula,

temporoparietal junction SPET studies (Ebmeier et al 1993; Yuasa et al, 1995)

– replicate finding of increased activity in medial prefrontal cortex/ anterior cingulate (ACC)

ACC strongly engaged in response selection, eg in Stroop task

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Psychomotor poverty and excitation

Psychomotor poverty:

– Poverty of speech

– Flat affect, anhedonia

– Decreased voluntary activity

Psychomotor excitation

– Pressure of speech

– Excited or irritable mood

– Motor hyperactivity

Abnormalities of the rate at which the mind generates thoughts, feelings and actions

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21Psychomotor poverty & excitation: context

Psychomotor poverty– Schizophrenia

(negative symptoms)– Retarded depression– Frontal lobe injury or

degeneration– Basal ganglia

degeneration (eg Parkinson’s disease

Psychomotor excitation– Mania– Acute schizophrenia– Basal ganglia

degeneration eg Huntingtons’ disease

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22Neuropsychological correlates of psychomotor poverty

Associated with – impaired memory, – Abstraction– Initiation and planning of activity

Decreased verbal fluency (Liddle & Morris, 1992; Norman et al 1997)

Increased RT in choice RT tasks (Ngan & Liddle, 2000)

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23Regional cerebral activity and psychomotor poverty

Liddle et al, 1992

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Psychomotor poverty and brain structure

In schizophrenia; some studies report psychomotor poverty is associated with ventricular enlargement (Lewis, 1990)

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25Neurochemistry & pharmacology of psychomotor poverty

Dopamine metabolism decreased (van Praag & Korf, 1971)

Stimulants can reduce apathy (Marin et al 1995)

Dopamine blocking antipsychotics can exacerbate psychomotor poverty (van Putten et al, 1990)

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26Neurochemistry & pharmacology of psychomotor excitation

Drugs that promote dopaminergic neurotransmission (eg amphetamine) produce psychomotor excitation in healthy people (Jaobs and Silverstone, 1986)

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Depression & Elation

Depression

– Low mood disproportionate to circumstances

– Sad facial expression, voice, posture

– Anhedonia

– Cognitive distortions –negative bias, including low self-esteem, guilt, hopelessness, suicidal thought

– Somatic symptoms (loss of sleep, appetite, libido etc)

– Sometimes associated with psychomotor poverty

Elation

– Euphoric mood

– Animated expression

– Elevated self-esteem and optimism

– Decreased need for sleep

– often associated with psychomotor agitation

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Mood disorders

Depression can occur in– Major depressive disorder (15-20% of pop)– Bipolar affective disorder (2% of pop)– Brain injury or degeneration– Drug induced mood disorder– Schizophrenia (depression in >50% of

cases)

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29Neuropsychological correlates of depression

Processing bias, preferential recall or attention to negative material (Gotlib, 1991)

Decreased speed of processing (Weingartner et al, 1981)

Impaired declarative memory (Zakzanis et al, 1998)

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Brain structure and mood disorders

Decreased grey matter in (sub-genual) anterior cingulate cortex in bipolar disorder and in major depression (Drevetts et al 1997)

Decreased hippocampal volume associated with duration of illness (Sheline et al, 1996). Possibly due to damage by elevated cortisol during acute episodes

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Regional cerebral activity and depression

decreased activity in lateral prefrontal cortex resolves as symptoms resolve (Baxter et al 1989).

overactivity in anterior cingulate during acute episodes (Mayberg et al, 1998)

evidence underactivity in anterior cingulate and medial prefrontal cortex in those prone to relapse and also in cases that respond poorly to treatment (Bench et al, 1992)

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32Regional cerebral activity associated with elation

Global increase in regional brain activity during manic episodes (elation + psychomotor excitation) (Baxter et al 1985)

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33Regional cerebral metabolism in bipolar disorder (Baxter et al 1985)

• Depression

• Mania

• Depression

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34Neurochemistry and pharmacology of mood disorders

Depression – Depression is decreased by drugs that enhance

monoamine neurotransmission eg SSRIs such as fluoxetine (Prozac) & SNRIs such as venlafaxine – this suggests that serotonin and noradrenaline neurotransmission is under-active in depression, but evidence is inconclusive

– Cortisol regulation is disrupted– maybe this is the core biochemical abnormality

Elation– Associated with increased dopamine

neurotransmission

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Bipolar affective disorder

Genetic influence– High concordance of bipolar affective disorder in monozygotic twins

between 0.67 and 0.85 (Glahn et al. 2004)-indicate environmental factors must have a role to play.

– Occurs around the world at a consistent prevalence, suggests alleles have been present for a long time.

Why does this gene survive? Does it pose a benefit. As an analogy, sickle cell trait can lead to illness but is recessive and helps resistantance to malaria.

– In low doses the symptoms of hypomania could be advantageous: increase in energy, faster thoughts, less sleep.

– Rates of mood disorders elevated among creative individuals (Richards and Kinney, 1989; Jamison, 1989)

– Individuals with bipolar traits more likely to be leaders within social groups (Gardner, 1982)

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Anxiety

Feeling of unease, dread, fear together with symptoms reflecting over-activity on the sympathetic nervous system– Generalised anxiety disorder – Panic disorder - brief dramatic episodes– Specific phobias eg fear of spiders– Agoraphobia - fear of public places– Post-traumatic stress disorder– Obsessive-compulsive disorder

Anxiety disorders frequently coexist, and are often associated with depression

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37Regional cerebral activity associated with anxiety

Provocation of anxiety produces activation of frontal, limbic and paralimbic cortex in patients and in healthy people

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Pharmacology of anxiety

Benzodiazepines (which promote GABA activity) – effective anxiolytics but addictive

Antidepressants are also effective anti-anxiety drugs

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Concepts of schizophrenia

Characteristic symptoms– Positive – presence of abnormal mental activity

Reality distortionDisorganization

– Negative – diminution of normal mental activityPsychomotor poverty

Many other symptoms: psychomotor excitation; depression

Onset tends to occur early in adult life

Deterioration in function (variable in degree)

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Reality distortion

Delusions– *Thought insertion, withdrawal, broadcast– *Control – made will, made acts, made affect– *Somatic passivity– *Delusional perception– Persecution etc

Hallucinations– *Third person auditory (commenting, discussing); Audible

thought – Second person auditory– Olfactory, visual, tactile

* Schneider’s first rank symptoms

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Age of onset

male

female

10 20 30 40 50 years

From Jennen-Steinmetz et al 1997

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Characteristic time course

1st acute epidsode

prodrome relapse residual phase

relapse

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ICD 10 diagnostic criteria

At least one strongly characteristic symptom– Schneiderian first rank symptom (eg 3rd person hallucination;

delusion of control.)– Persistent bizarre delusion

OR two less characteristic symptoms– Other hallucinations– Formal thought disorder– Catatonia– Negative symptoms

Duration: at least one month

Exclusion of affective psychosis; exclusion of overt brain disease, or drug toxicity

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Aetiology : predisposing factors

Genes– twin concordance: MZ 45%, DZ 12-15%– adoption: risk is determined by biological

parent

Intra-uterine insult– Maternal viral infection– Maternal starvation– Maternal stress

Birth complications

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Aetiology: precipitating factors

Stress

Drug abuse- – amphetamine, cocaine, – marihuana etc

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Brain structure in schizophrenia

Ventricular enlargement (but effect size is only 0.6 – therefore most cases in nromal range)

Loss of grey matter in many brain regions, most marked in medial temporal lobe and thalamus

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•Executive function, attention, memory (e.g. Green, 1998)

• Variation over time and between patients is complex, symptoms tend to be worse during acute episodes, but also present during remission

Cognitive deficits in schizophrenia

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Pharmacology

Typical antipsychotics: eg chlorpromazine; haloperidol: block dopamine - alleviate reality distortion, disorganization and excitation

Atypical antipsychotics: block dopamine + other transmitters (eg serotonin). Slightly greater efficacy against positive symptoms; moderate effect on negative symptoms, small improvment in cognition

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Bipolar mood disorder

Depressive episode– Depressive syndrome

Sad mood, anhedonia Negative thoughts,

hopelessness, suicidality Guilt (can be delusional) Somatic symptoms

often accompanied by: – Psychomotor poverty

(retarded depression)or – Psychomotor excitation

(agitated depression)

Manic episode– Psychomotor excitation

Elation or irritability Pressure of speech Overactivity, reduced

need for sleep

often accompanied by:

– Grandiose reality distortion

Grandiose delusions Mood congruent

hallucinations

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Genetics

• Concordance for affective disorders is 67% in monozygotic twins and in 20% in dizygotic twins (Bertelson et al., 1977), genetic factors for unipolar depression related by partially distinguishable

Aetiology of bipolar disorder

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Ventricular enlargement (e.g. Pearlson & Veroff, 1981) usually less marked than in schizophrenia

• Decreased grey matter in anterior cingulate (Drevets et al., 1997)

Anatomy of bipolar disorder

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Pharmacology of bipolar disorder

Antipsychotics (which block dopamine): effective in treating psychomotor excitation and reality distortion during acute episodes of mania

Mood stabilizers (eg Lithium, and various anticonvulsants)

Antidepressants have a limited role as they promote mania

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Psychopathy

• A personality disorder (enduring throughout adult life) with two main groups of features:

– Callous disregard for others (Lack of empathy; lying; manipulative; glib; shallow affect; lack of remorse or guilt)

– Impaired regulation of behaviour (impulsivity, irresponsibility; need for stimulation)

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Aetiology of psychopathy

Genes– Concordance for antisocial personality disorder is

51% in monzygotic twins and 22% in dizygotic twins

Brain injury: – damage to frontal lobes in infancy can lead to

psychopathy– Frontal damage in adulthood can produce

pseudopsychpathy – impaired behavioural regulation without callousness (Phineas Gage)

Adverse social circumstances ?

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55Cognition and information processing in psychopathy

Psychopaths do not show widespread cognitive impairments (Hart et al., 1990), but there is evidence of orbital frontal cortex dysfunction (Lapierre et al., 1995)

Reaction time to affect-laden words reduced in healthy people but not psychopaths in lexical decision task (Williamson et al, 1991); less limbic activation while processing affect laden words (Kiehl et al 2001)

Abnormal ERPs for response inhibition (Kiehl et al., 2000) and target detection (Kiehl et al 1999)

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Psychopaths exhibit a large fronto-central negativity during stimulus detection tasks that is also present in patients with anterior temporal lobe lesions (Kiehl et al., 1999)

Kiehl et al. Yamaguchi & Knight (1993) Johnson (1989)

400 800ms5001000ms

NonpsychopathsControls

Controls

PsychopathsTemporal lobedamaged patients

Temporallobectomy

Parietal lobedamaged patients