Psychiatric disorders

1. Psychiatric disorders • Peter Liddle • Chris Rorden

2. 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

3. 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.

4. Major symptom clusters • Reality distortion • Disorganization • Psychomotor poverty • Psychomotor excitation • Depression • Euphoria • Anxiety

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. Neuropsychological 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)

12. Regional 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

13. Neurochemistry 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)

14. 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

15. 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)

16. 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

17. Neuropsychological 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)

18. Regional cerebral activity and disorganization Liddle et al, 1992

19. Regional 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

20. Psychomotor poverty: Poverty of speech Flat affect, anhedonia Decreased voluntary activity Psychomotor excitation Pressure of speech Excited or irritable mood Motor hyperactivity Psychomotor poverty and excitation Abnormalities of the rate at which the mind generates thoughts, feelings and actions

21. 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 Psychomotor poverty & excitation: context

22. Neuropsychological 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)

23. Regional cerebral activity and psychomotor poverty Liddle et al, 1992

24. Psychomotor poverty and brain structure • In schizophrenia; some studies report psychomotor poverty is associated with ventricular enlargement (Lewis, 1990)

25. Neurochemistry & 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)

26. Neurochemistry & pharmacology of psychomotor excitation • Drugs that promote dopaminergic neurotransmission (eg amphetamine) produce psychomotor excitation in healthy people (Jaobs and Silverstone, 1986)

27. 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 Depression & Elation

28. 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)

29. Neuropsychological 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)

30. 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

31. 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)

32. Regional cerebral activity associated with elation • Global increase in regional brain activity during manic episodes (elation + psychomotor excitation) (Baxter et al 1985)

33. Regional cerebral metabolism in bipolar disorder (Baxter et al 1985) • Depression • Mania • Depression

34. Neurochemistry 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

35. 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)

36. 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

37. Regional cerebral activity associated with anxiety • Provocation of anxiety produces activation of frontal, limbic and paralimbic cortex in patients and in healthy people

38. Pharmacology of anxiety • Benzodiazepines (which promote GABA activity) – effective anxiolytics but addictive • Antidepressants are also effective anti-anxiety drugs

39. Concepts of schizophrenia • Characteristic symptoms • Positive – presence of abnormal mental activity Reality distortion Disorganization • Negative – diminution of normal mental activity Psychomotor poverty • Many other symptoms: psychomotor excitation; depression • Onset tends to occur early in adult life • Deterioration in function (variable in degree)

40. 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

41. Age of onset 10 20 30 40 50 years From Jennen-Steinmetz et al 1997

42. Characteristic time course prodrome 1st acute epidsode relapse relapse residual phase

43. 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

44. 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

45. Aetiology: precipitating factors • Stress • Drug abuse- • amphetamine, cocaine, • marihuana etc

46. 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

47. Cognitive deficits in schizophrenia • 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

48. 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

49. 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 Bipolar mood disorder

50. Aetiology of bipolar disorder • 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