PSYCHOACTIVE DRUGS Drugs have revolutionized psychiatric treatment since the 1950's. Most psychoactive drugs act stereospecifically on receptors, enzymes, or other active protein elements of the nerve cell (e.g., ion channnels, blocked by local anesthetics). Existence of a drug can lead to discovery of a mechanism (e.g., opiates, salicylates, chlorpromazine). The majority of psychoactive drugs affect synaptic transmission. Drugs can have synergystic (combinatorial) interactions with other drugs. (Some may be good, many are bad) Many drugs have side effects (We will talk about tardive dyskinesia, a side effect of long term treatment with antipsychotic drugs).

There are Two Classes of Neurotransmitter Receptors: Ionotropic Receptors, when activated by neurotransmitter, allow ions to cross the cell membrane via channels Metabotropic Receptors, when activated by neurotransmitter, trigger enzymatic activity The same neurotransmitter, e.g., glutamate or acetylcholine, can activate both ionotropic and metabotropic receptors Ionotropic receptors will be illustrated here

What brain abnormalities might underlie such a devastating disorder? Theories on the Mechanism(s) of Schizophrenia Genetic Vulerability: MZ (identical) twin concordance >4 X more likely than DZ (sibling) twins; MZ twins average 50% discordance rate suggesting environmental influences Experience-based Vulnerability: More frequent in lower socioeconomic classes; stress may precipitate relapse; social network an important buffering influence (often disrupted by schizophrenic’s own behavior)

Brain structure-based theories implicate frontal and medial temporal lobes * Ventricular enlargement: In effect this means that tissue adjacent to the ventricles shrinks--temporal lobe, hippocampus *Several reports of shrinkage of frontal lobes, fewer synapses per neuron, reduced dendritic field size in prefrontal brain regions *fMRI and PET (blood flow/metabolism) studies indicate “hypofrontality,” decreased activity of frontal lobes

Pharmacological treatment-based theories *From Chlorpromazine in the 1950s to the recent past, “typical” neuroleptic drugs, effective in schizophrenia had in common the blockage of the D 2 Dopamine receptor. (They differ in therapeutic and negative side effects.) * The Dopamine systems of the brainstem project to limbic (“mesolimbic”) and frontal cortical (“mesocortical”) brain regions. Both may be involved in Schizophrenia. *We won’t detail receptor actions because there will probably be more receptors when you’re MDs.

“Atypical” Antipsychotic Drugs: Affect both Dopamine and Serotonin Systems * These drugs may do better at controlling both positive and negative symptoms of schizophrenia * Some “atypicals” (e.g. clozapine) have high affinity for newly discovered D 4 Dopamine receptors * Atypicals appear Not to cause Tardive Dyskinesia

Drug Therapy for Schizophrenia: Medication alone is never the treatment for a patient Medications may be important components of a larger overall treatment plan

Proposed Brain Mechanisms Underlying Mood Disorders * While traumatic or stressful events can lead to symptoms of mood disorder, this is typically treated as a separate, usually transient “adjustment disorder with depressed mood.” * There are theories that some (or much) depression may arise in situations with poor social support, chronic stress, negative personal or occupational situations, etc. * As with schizophrenia, theories of the brain mechanisms underlying mood disorders have been driven by the mechanisms of action of effective drugs.

Proposed Brain Mechanisms Underlying Mood Disorders *One of the most common biological abnormalities in patients with major depression is hyperactivity of the hypothalamic-pituitary-adrenal axis, the stress response system. *Dexamethasone, a synthetic adrenal corticosteroid, normally suppresses pituitary adrenocorticotropic hormone (ACTH) release for 24 hours. *In depressed patients this suppression is often less pronounced or less prolonged. *There is also evidence for elevated levels of thyrotropin- releasing hormone (TRH) and other thyroid abnormalities in depression.

Drug-based Theories of Mood Disorders I * The initial treatments that were effective in treating many cases of depression had in common raising the levels of catecholamines (norepinephrine and dopamine) at the synapse (MAO inhibitors, reuptake blockers-- “tricyclic antidepressants). * These led to the Norepinephrine and Catecholamine (includes Dopamine) hypotheses of mood disorders. Reduced catecholamine availability at the synapse caused depressive disorders * These pharmacological phenomena take effect almost immediately, yet treatment may last 2 weeks or more before significant symptom remission occurs.

Drug-based Theories of Mood Disorders II * More recently, serotonin has been implicated in mood disorders. * Brain serotonin is low in many depressed patients and reduced levels of the serotonin metabolic breakdown product (5-HIAA) are common in cerebrospinal fluid. This is common among suicidal depressives. * Selective serotonin reuptake inhibitors (Prozac) are effective in restoring mood. * But why do they take so long to work?