Neuropsychiatric Disorders II - Lecture Notes

Neuropsychiatry

• Neuropsychiatry addresses the psychiatric consequences of neurological diseases, the neurological basis of psychiatric illnesses, and neurological symptoms that don't match underlying neuropathology.

Paralytic Dementia and Syphilis

• Early 20th century: Paralytic dementia was characterized by delusions, grandiosity, euphoria, poor judgment, and impulsivity.
• 1911: Hideyo Noguchi discovered that paralytic dementia was caused by brain damage due to syphilis, a sexually transmitted bacterial infection.

Prevalence of Psychiatric Disorders

• Psychiatric disorders are mainly diagnosed based on behavioral symptoms.
• Over one-third of the U.S. population reports symptoms of a major psychiatric disorder at some point in life.
• Depression is more prevalent in females, while drug dependency and alcoholism are more prevalent in males.

Schizophrenia

• Major symptoms include auditory hallucinations, personalized delusions, changes in affect, and cognitive impairments.
• Positive symptoms: Hallucinations, delusions, and excited motor behavior.
• Negative symptoms: Slow and impoverished thought and speech, emotional and social withdrawal.
• Genetics: The closer the relationship to someone with schizophrenia, the higher the risk of developing it.
• Genetic analyses suggest over 100 genes influence schizophrenia risk.

Lobotomy

• Lobotomy is a discredited neurosurgical treatment that involves severing connections in the prefrontal cortex.
• Moniz's work was influenced by Fulton and Jacobsen's experiments with chimpanzees. Frontal lobectomies in chimpanzees resulted in reduced "frustrational behaviour" and increased timidity.

Psychopharmacology

• Chlorpromazine was initially developed as an anesthetic but found to reduce the positive symptoms of schizophrenia.
• It was initially promoted as a "lobotomy in a bottle."

Dopamine Hypothesis of Schizophrenia

• Antipsychotic drugs block postsynaptic dopamine receptors, especially D2 receptors.
• Dopamine hypothesis: Schizophrenia is caused by an excess of dopamine release or dopamine receptors.

Amphetamine and Schizophrenia

• Large doses of amphetamine can induce symptoms of paranoia, delusions, auditory hallucinations, suspiciousness, and bizarre motor behavior, resembling schizophrenia (amphetamine psychosis).
• Amphetamine exacerbates schizophrenia symptoms.
• Amphetamine promotes dopamine release and prolongs its action by blocking reuptake.

Neurochemistry of Schizophrenia

• PCP is an NMDA receptor antagonist; it blocks the NMDA receptor's central calcium channel.
• Treating monkeys with PCP induces a schizophrenia-like syndrome.
• Ketamine, another NMDA receptor antagonist, has similar effects.
• Glutamate hypothesis of schizophrenia.

Ventricular Enlargement

• Many people with schizophrenia have enlarged cerebral ventricles, especially the lateral ventricles.
• Ventricular enlargement predicts later development of schizophrenia in adolescents.
• The extent of enlargement relates to responsiveness to antipsychotic drugs; more-enlarged ventricles lead to poorer response.

Ventricular Enlargement and Genetics

• Atrophy in the hippocampus and amygdala could cause ventricular enlargement in schizophrenia.

Hypofrontality Hypothesis

• People with schizophrenia show less metabolic activity in the frontal lobes.
• The hypofrontality hypothesis suggests that frontal lobe dysfunction results in schizophrenia.

Aberrant Salience Hypothesis of Schizophrenia

• Hyperdopaminergic state leads to aberrant assignment of salience to experiences.
• Dopamine mediates the conversion of neural representations of stimuli into salient events.
• Symptoms arise from the aberrant assignment of salience to external objects and internal representations.
• Antipsychotics reduce positive symptoms by attenuating aberrant motivational salience via blockade of dopamine D2 receptors.

Depression Symptoms

• Clinically significant depression: Unhappy mood, loss of interests, energy, and appetite; difficulty concentrating; and restless agitation.
• Depression can lead to suicide.
• Many suicides are impulsive acts or prompted by time-limited crises.
• One study found that only 6% of people prevented from jumping off the Golden Gate Bridge later committed suicide.

Epidemiology of Depression

• Around 8% of adults in the U.S. suffer from severe unipolar depression annually, and 5% suffer from mild forms.
• Around 20% of adults experience severe unipolar depression at some point in their lives.
• Prevalence rates are similar in Canada, England, France, and many other countries.

Electroconvulsive Therapy (ECT)

• ECT is the intentional induction of a large-scale seizure.
• Originally used unsuccessfully for schizophrenia, it was later found to rapidly reverse severe depression.
• ECT is now used for treatment-resistant depression.

Monoamine Hypothesis

• Monoamine hypothesis was suggested by the first antidepressants, which were inhibitors of monoamine oxidase (MAO).
• MAO inactivates norepinephrine, dopamine, and serotonin.
• MAO inhibitors raise monoamine levels in synapses, suggesting depressed people lack sufficient stimulation at those synapses.
• Reserpine, which reduces norepinephrine and serotonin release, can cause profound depression.
• Tricyclics inhibit the reuptake of monoamines, boosting synaptic activity.

SSRIs and Ketamine

• Selective serotonin reuptake inhibitors (SSRIs) like Prozac are a major class of modern antidepressants.
• SSRIs are more effective than MAO inhibitors and tricyclics with fewer side effects.
• Ketamine, a glutamate receptor antagonist, relieves depression almost instantly.
• Hallucinogens like psilocybin can rapidly relieve depression.

Mechanism of Action

• Neurons reabsorb excess neurotransmitters like norepinephrine or serotonin via a reuptake mechanism.
• In depression, this reuptake process is too active.
• Antidepressants block the reuptake process, enabling NE or 5HT to remain in the synapse longer.

Cushing’s Syndrome and Depression

• High levels of circulating glucocorticoids (e.g., cortisol) can cause depression.
• Cushing’s syndrome may result from hormone-secreting tumors or therapeutic treatments with synthetic glucocorticoids.
• Depression appears early in over 85% of people with Cushing’s syndrome.

HPA Axis

• The hypothalamic-pituitary-adrenal system is involved in depression.
• ACTH: adrenocorticotropic hormone
• CRH: corticotropin-releasing hormone
• Circulating cortisol levels are usually higher in people with depression.

Sleep in Depression

• Difficulty falling asleep and inability to maintain sleep are common.
• People with major depressive disorders show a reduction in slow-wave sleep (SWS).
• They enter REM sleep sooner after sleep onset.
• Increased amount of REM sleep occurs during the first half of sleep.

The Depressed Brain

• The brain circuit involved in unipolar depression includes structures such as the prefrontal cortex (PFC), hippocampus, amygdala, and subgenual cingulate.