Chapter 18Biopsychology of Psychiatric

Disorders

The Brain Unhinged

Psychiatric Disorders

• AKA psychological disorders• Disorders of psychological function that require

treatment by a mental health professional• Neuropsychological disorders - a product of

dysfunctional brains – but so are psychiatric disorders

• Historically:– Neuropsychological disorders – brain problem– Psychiatric – mind problem

Psychiatric Disorders

• More influenced by experiential factors

• Tend to be the product of more subtle forms of brain pathology– Underlying dysfunction may yet to be

identified, but are suggested by the effectiveness of treatments

• Tend to be less well understood

Psychiatric Disorders

• What are the advantages and disadvantages of societal acceptance of psychological disorders as diseases with a biological basis?

• Are there some conditions for which this acceptance already exists?

Anxiety Disorders

• Anxiety – fear in the absence of threat

• Anxiety disorder – when anxiety interferes with normal functioning– Accompanied by physiological symptoms –

tachycardia, hypertension, sleep disturbances, nausea, etc.

• Most prevalent psychiatric disorders

Anxiety Disorders

• Generalized – stress and anxiety in the absence of a causal stimulus

• Phobic – similar to generalized, but triggered by a stimulus

• Panic disorders – may occur with other disorders, but also alone

• Obsessive-compulsive disorders (OCDs) – obsessive thoughts alleviated by compulsive actions

• Posttraumatic stress disorder

Treatment of Anxiety Disorders

• Benzodiazepines (Librium, Valium)– Also used as hypnotics, anticonvulsants, muscle

relaxants

– GABAA agonists – bind to receptor and facilitate effects of GABA

– Highly addictive

• Serotonin agonists (Buspirone, SSRIs)– Reduce anxiety without sedation and other side

effects

The GABA Receptor

Animal Models of Anxiety

• Assess anxiolytic potential of drugs - assume that defensive behaviors are motivated by fear, and that fear and anxiety are comparable– Elevated-plus-maze: time in open arms indicates less

anxiety– Defensive-burying: More time burying, more anxiety– Risk-assessment test: Time freezing and assessing

risk indicate anxiety level• Validated by effectiveness of benzodiazepines –

but not all anxiety treated with such drugs

Neural Bases of Anxiety Disorders

• Drugs suggest a role for serotonin and GABA

• Amygdala, due to its role in fear and defensive behavior, thought to be involved– No pathology yet identified

Affective Disorders

• Depression – normal reaction to loss, abnormal when it persists or has no cause

• Mania – opposite of depression

• Bipolar affective disorder

– Depression with periods of mania

• Unipolar – depression only

– Reactive – triggered by negative event

– Endogenous – no apparent cause

Causal Factors in Affective Disorders

• Affective disorders are very common– ~6% suffer from unipolar affective disorder at some

point, ~1% from bipolar

• Genetics– Concordance rate higher for bipolar than unipolar

• Stressful experiences – More stress reported by those seeking treatment for

depression than controls

Antidepressant Drugs

• Monoamine oxidase inhibitors (MAOIs)– Prevent breakdown of monoamines– Must avoid foods high in tyramine – ‘cheese effect’

• Tricyclic antidepressants– Block reuptake of serotonin and norepinephrine– Safer than MAOIs

• Selective monoamine reuptake inhibitors• Lithium – mood stabilizer

– Not a drug – treats bipolar

Selective monoamine reuptake inhibitors

• Selective serotonin-reuptake inhibitors (SSRIs)– Prozac, Paxil, Zoloft– No more effective than tricyclics, but side effects are

few and they are effective at treating other things

• Selective norepinephrine-reuptake inhibitors (SNRIs)– Also effective

Effectiveness of Drug in Treating Affective Disorders

• Results are comparable with MAOIs, tricyclics, and SSRIs– About 50% improve, compared to 25% of

controls

• Drugs help those experiencing depression, but do not prevent future episodes

Monoamine Theory of Depression

• Underactivity of serotonin (5HT) and norepinephrine (NE)– Consistent with drug effects– Up-regulation of receptors at autopsy of

depressed individuals consistent with this

• Problem with theory – not all respond to monoamine agonists

Diathesis-Stress Model

• Inherited genetic susceptibility (diathesis) + stress = depression

• Support is indirect– Depressed people tend to release more

stress hormones– Fail dexamethasone suppression test –

normal negative feedback on stress hormones not functioning

Sleep Deprivation

• More than 50% of depressed patients improve after one night of sleep deprivation.

• Short-lasting: depression returns when normal sleep pattern resumes.

• Not explained by any theory. • What does this suggest?

Brain Damage and Unipolar Depression

• Amygdala• Prefrontal cortex

– Both involved in perception and experience of emotion

• Terminal structures of the mesotelencephalic DA system– Consistent with anhedonia (lack of pleasure)

experienced by the depressed

Tourette’s Syndrome

• A disorder of tics, involuntary movements or vocalizations

• Begins in childhood• Major genetic component• Many also have signs of ADHD and/or OCD• No animal models, no genes identified, imaging

difficult due to tics

Tourette’s Syndrome

• Usually treated with neuroleptics – although effectiveness is not well-established

• Effectiveness of D2 blockers suggests abnormality in basal ganglia-thalamus-cortex feedback circuit

Schizophrenia• “splitting of psychic functions”

– Refers to the breakdown of integration of emotion, thought, and action

• Affects 1% of the population• A diverse disorder – multiple types exist with

varied profiles• Some symptoms: delusions, hallucinations, odd

behavior, incoherent thought, inappropriate affect– Only 1 needed for 8 months for diagnosis

Causal Factors in Schizophrenia

• Clear genetic basis– Inherit an increased risk for the disorder

• Multiple causes– Several different chromosomes implicated– Associated with various early insults – infections,

autoimmune reactions, toxins, traumatic injury, stress

• Appears that interference with the normal development of susceptible individuals may lead to development of the disorder

Antipsychotic Drugs

• Much of our understanding of schizophrenia is a consequence of the drugs that are able to treat it

• Chlorpromazine – calms many agitated schizophrenics and activates many emotionally blunt

• Reserpine – also found to be effective• Both drugs are not effective for 2-3 weeks and

Parkinson-like motor effects are seen– Suggesting a role for what neurotransmitter?

Dopamine (DA) Theory of Schizophrenia

• 1960 – link between DA and Parkinson’s Disease established

• Side effects of antipsychotic drugs suggests role for dopamine: Drugs work by decreasing DA levels, disorder is a consequence of DA overactivity– Reserpine depletes brain of DA and other monoamines by

making vesicles leaky– Amphetamine and cocaine are DA agonists and produce

psychosis– Chlorpromazine antagonizes DA activity by binding and blocking

DA receptors

Dopamine (DA) Theory of Schizophrenia

• In general, the higher affinity a drug has for DA receptors, the more effective it is in treating schizophrenia

• Haloperidol – an exception– While most antipsychotics bind to D1 and D2

receptors, it and the other butyrophenones bind to D2

• Degree that neuroleptics bind to D2 receptors is correlated with their effectiveness

Problems with the D2 Theory

• Clozapine, an atypical and effective neuroleptic, acts at D1, D4, and serotonin receptors. But – some binding to D2

• Neuroleptics act quickly at the synapse, but don’t alleviate symptoms for weeks.– Indicates some slow-acting change must occur.

• Schizophrenia associated with brain damage.– Little damage to DA circuitry– Damage not explained by DA theory

• Neuroleptics are only effective for some

Problems with the D2 Theory

• Positive symptoms - presence of abnormal– incoherence, hallucinations, delusions

• Negative – absence of normal– flat affect, cognitive deficits, little speech

• Conventional neuroleptics (D2 blockers) mainly effective at treating positive

• Negative – might be caused by brain damage• May be best to think of schizophrenia as multiple

disorders with multiple causes