PS201418 : Biological Psychology

1
PS2014/18 Biological Psychology
Biochemical basis of psychiatric disorders 1
Psychosis and schizophrenia
2
The problem with schizophrenia
its symptoms are numerous, its presentations are
diverse, its cause is unknown and its response to
treatment is unsatisfactory From PJ McKenna,
Schizophrenia and Related Disorders, 1997
3
Symptoms of psychosis

• Abnormal ideas
• delusions (mood, persecution, grandiose,
  hypochondriacal)

• Abnormal perceptions
• hallucinations (mainly auditory)

• Formal thought disorder
• derailment, loss of goal, neologisms, poverty of
  speech content

• Motor, volition and behavioural disorder
• catatonia, abnormal posture, avolition, mutism,

• Emotional disorders
• affective flattening, emotional withdrawal,
  anhedonia.

4
Psychosis and schizophrenia
Amphetamine
Drug induced
Phencyclidine (angel dust)
LSD
Psychosis
Neurological
Temporal lobe injury
Simple delusional disorder
Pathological
Schizoaffective disorder
Paraphrenia
Psychiatric
Schizotypal disorder
Puerperal psychosis
Schizophrenia
5
Dopamine Theory of Schizophrenia

• Amphetamine causes symptoms very similar to
  positive symptoms of schizophrenia

• Dopamine antagonists are the best treatment for
  schizophrenia
• Some evidence of increased dopamine function in
  schizophrenics

• BUT
• Amphetamine does not cause negative symptoms
• Dopamine antagonists do not treat negative
  symptoms
• Changes in dopamine function may be a response to
  long term drug treatment

• Hyperactivity in mesolimbic dopamine positive
  symptoms
• Hypoactivity in mesocortical dopamine negative
  symptoms

6
Schizophrenia overactivity of mesolimbic
dopamine
7
Supporting evidence for dopamine theory

• Clinical potency of typical antipsychotics
  parallels their pharmacological potency in
  blocking dopamine receptors
• Parkinsonian side effects of typical
  antipsychotics
• Psychotic side effects of Parkinsons disease
  treatments
• Increased D-2 (but not D-1) receptors in striatum
• Some reports of increases in D-4 receptors
• Mesolimbic dopamine in animal models (latent
  inhibition, prepulse inhibition)

8
Dopamine and schizophrenia Psychological
considerations
9
Biochemical Changes in Schizophrenia

• Decreased dopamine metabolites in cerebrospinal
  fluid
• Increased striatal D-2 receptors
• Decreased mRNA for D-3 and D-4 receptors in
  cortical regions
• Decreased cortical glutamate
• Increased cortical glutamate receptors
• Decreased glutamate uptake sites in cingulate
  cortex
• Decreased mRNA controlling GABA synthesis in
  prefrontal cortex
• Increased GABA-A binding sites in cingulate cortex

10
Alternative theoriesfor the neurochemistry of
schizophrenia

• Increased 5HT function
• the 5HT agonist lysergic acid diethylamide (LSD)
  causes hallucinations
• many antipsychotic drugs also affect 5HT systems
• may be modulatory of dopamine function

• Decreased cortical glutamate
• glutamate antagonists induce psychosis
• much of the known pathology is in glutamatergic
  areas

11
Pharmacological treatment of schizophrenia

• Chlorpromazine drug used to treat surgical
  shock.
• Patients reported a feeling of well-being
  therefore tried on psychotic patients!!!
• Found to reduce psychotic symptom.

• It has since been found that chlorpromazine is
  an antagonist at dopamine receptors.

Are other dopamine receptor antagonists also
antipsychotic? Is dopamine receptor blockade
necessary for antipsychotic activity?
Haloperidol, Sulpiride, Amisulpiride, Benzamide
12
Typical antipsychotics

• Typical antipsychotics
• Mostly dopamine D2 receptor antagonists
  (neuroleptics)
• Reasonably effective against positive symptoms,
  but not against negative
• Severe motor side effects (extrapyramidal side
  effects)
• 40 50 of patients may not show improvements
• e.g. chlorpromazine, haloperidol

• Problems with antipsychotic medication
• Effectiveness of drugs
• Compliance
• Side effects

13
To block or not to block D2 receptors?That is
the question.
14
Clozapine
Good antipsychotic potency, but minimal
extrapyramidal side effects. Effective in
patients who are refractory to other
antipsychotics Reduces negative symptoms

• But
• Causes leukopenia and agranulocytosis
• Causes excessive salivation
• Can cause transient hyperthermia

• Used in patients who are refactory to other
  treatments
• Blood cell count must be monitored weekly
• this adds substantially to the cost

15
Atypical antipsychotic drugs

• Atypical antipsychotics
• Antipsychotic, but without the extrapyramidal
  side-effects
• Effective against negative as well as positive
  symptoms
• Act on many different receptor types (e.g. 5HT2)
• e.g. clozapine, olanzipine, pimozide,
  risperidone
• BUT
• Can be quite variable effects in different
  patients
• May not work as quickly as typicals
• Many cause weight gain (probably due to
  anti-histamine action)
• Cause excessive salivation

16
Pharmacological profile of some antipsychotic
drugs
17
Treatment of schizophrenia

• First-line acute and maintenance treatment
  generally uses atypical antipsychotics
• Use of typical antipsychotics mainly restricted
  to acute uncooperative patients where rapid onset
  is required
• Typical antipsychotics also used for
  non-compliant patients who require monthly
  injections of a depot antipsychotic.

Intramuscular and depot formulations of atypical
antipsychotics are not yet available, but both
are under development.
18
Non-compliance, relapse and the revolving door

• Even in patients where antipsychotics are
  effective, discontinuing causes relapse at the
  rate of 10 per month
• However the adverse side effects means that many
  patients stop taking medication and relapse into
  psychosis
• Many patients select the risk of relapse rather
  than the subjectively unacceptable side effects

Therefore reducing side effects is an important
goal
19
Antipsychotic drugs

• Typical antipsychotics
• Chlorpromazine (largactil)
• Thioridizine (mellaril)
• Fluphenazine (prolixin)
• Loxapine (loxitane)
• Haloperidol (haldol)
• Molindone (moban)

• Atypical antipsychotics
• Chlozapine (clozaril)
• Risreridone (Risperidol)
• Remoxipride
• Seroquel
• Olanzapine

20
Affective disorders and antidepressant drugs
Biochemical basis of psychiatric disorders 2
Mood disorders

• Unipolar depression (major depression)
• Depression without a history of mania
• Bipolar disorder (formerly called manic
  depression)
• Alternating periods of mania and depression

21
Summary from PS2015

• Interaction between genetic predisposition and
  precipitatory factors leads to neurotransmitter
  imbalances
• Imbalances in serotonin and noradrenalin
• Serotonin underactive in both depression and
  mania
• Noradrenalin underactive in depression,
  overactive in mania.
• Main pharmacological treatments use drugs which
  increase noradrenalin and serotonin
• Abnormal levels of cortisol (effect on sleep-wake
  cycle)
• Abnormal melatonin (SAD)
• We will explore this in greater depth in PS2014/8

22
Symptoms of depression

• A major depressive episode is a period marked by
  at least five symptoms of depression lasting for
  two weeks or more
• depressed mood most of the day
• markedly diminished interest in activities
• significant weight loss or weight gain
• psychomotor agitation or retardation
• fatigue or loss of energy
• feelings of worthlessness or excessive guilt
• reduced ability to think or concentrate
• recurrent thoughts of death or suicide

23
Antidepressants

• Pre 1950s
• Main treatment was electroconvulsive therapy
  (ECT) or, in extreme cases, brain surgery
• ECT works in some but not all cases
• 1950s - First pharmacological treatment -
  Iproniazid
• Used as an antibacterial agent (although not very
  effective)
• Reported to elevate mood
• Nathan Kline (1956) found that it reduced
  depression in a variety of patient groups
• Marketed as the first antidepressant drug
  (Marsilid)
• Known to be a monoamine oxidase inhibitor (MAOI)

24
Reserpine

• Reserpine extracted from Indian snake root
  plant
• Used as a tranquiliser, and for treating high
  blood pressure (hypertension)
• Found to produce severe, often suicidal,
  depression
• In 1960s it was found that reserpine depletes
  monoamines in the brain.

25
Monoamine theory of depression
Joseph Schildkraut (1965) some if not all
depressions are the consequence of an absolute or
relative deficiency of catecholamines. Brought
several pharmacological findings together.
The depressed state is brought about by a
lowering of monoamine levels in the brain

• Noradrenaline, serotonin (5HT), dopamine

26
Noradrenergic hypothesis

• Studies of noradrenaline metabolite (MHPG) in CSF
  or blood of depressed patients showed variable
  results.
• No consistent decrease as would be predicted.
• Successful treatment with antidepressants often
  associated with decreased MHPG
• Little evidence of decreased noradrenaline or
  noradrenaline function in post mortem brains of
  depressed people

27
Serotonin hypothesis
Schildkraut underestimated the importance of
serotonin

• Serotonin involved in pain sensitivity,
  emotionality and response to negative
  consequences
• Some studies showed the serotonin metabolite,
  5-HIAA to be reduced in CSF of depressed patients
• But other studies refute this.
• Low 5-HIAA associated with aggressive hostile and
  impulsive behaviour as in violent suicide
  attempts
• Decreases in serotonin levels reported in post
  mortem brains of some depressed patients.