Lecture 31: Psychopharm Part 3

Cognitive Behavioral Therapy (CBT)

20 sessions can be as effective as taking SSRIs. Aims at correcting negative thinking. Reduces stress and fear, improves interpersonal relationships. Cycle of depression: negative thoughts (there is no point in trying) --> low mood (feeling guilty, discourages, inadequate, worthless) --> reduced behavior (becomes less active, avoid people and stimulation) --> negative thoughts.

Transcranial Magnetic Stimulation (TMS)

A milder form of treatment that involves a current that is delivered through the skull. Appears to be quite affective for some individuals. Less effective in reducing symptoms

Cushing's Syndrome

Abnormally high levels of circulating adrenal glucocorticoids; may be due to hormone secreting tumors or synthetic glucocorticoid treatment for other conditions. 85% of individuals with Cushing's present with symptoms of depression prior to any other symptoms of the syndrome. These findings support the idea that dysfunction of the HPA axis may be involved in depression, perhaps part of depression induced stress reaction

Neurotransmitters in Excess in Depression

Acetylcholine, acetylcholinesterase inhibitor can induce symptoms of depression. Substance P, chronic pain sufferers are often depressed, and depressed people often complain of pains. Corticotropin releasing hormone (CRH), due to overactive stress response.

Treatment of Substance Abuse

Agonist substitution, antagonistic treatment, and aversive treatment.

Imaging Technology

Allows us to make observations in the living brain in the clinical cohort and to use those functional differences to correlate functional differences with behavior (emergent function)

Tricyclics

Block reuptake to increase synaptic levels of serotonin and norepinephrine. Second generation of antidepressant drugs. Conform to the monoamine hypothesis: inhibit the reuptake of monoamines that functions to increase the amount of monoamines in the synapse. ex: Wellbutrin

Selective Serotonin Reuptake Inhibitors (SSRIs)

Block the reuptake of serotonin, having little effect on norepinephrine or dopamine synapses. Third generation. Prozac, zoloft, etc. While pharmacologically complex, these drugs block the reuptake of serotonin, so they function to increase levels of serotonin at the synapse. Generally more effective than MAOIs and tricyclics, have fewer side effects

Structural Brain Changes with Depression

Brains look different than healthy controls. Anatomical studies show thinner cortex, especially in the frontal lobes, and a smaller hippocampus. Hard to ascertain if these are a consequence of depression or if they're in fast a host factor (traits of a characteristic that affects susceptibility to a disease)

Electroconvulsive Therapy

Delivery of strong current to the brain. Thought to reduce functional connectivity between the prefrontal cortex and other brain areas. Can rapidly reduce symptoms of depression; after one session, patients can report significant improvement that persists. May be see as a last resort, but still an important too for treating severe drug-resistant depression.

Monoamine Hypothesis of Depression

Depression is caused by reduced activity of one or more monamine transmitters such as serotonin. Among monoamines, serotonin may play the most important role in depression.

Drugs Pharmacokinetics

Determines onset, duration of effect, and intensity. Dose response curves are a major too to assess relationships between drugs and their targets. ED50 = median effective dose; dose of a drug that produces a maximal effect in 50% of the population. Can compare these between drugs to assess relative potencies. LD50 = dose at which causes death in 50% of the population. Can compare ED50 to LD50 to determine therapeutic index. A drug with a wider index is safer, wider dosing range between an effective dose and a lethal dose.

Antagonistic Treatment

Drugs that block or counteract the positive effects of substances. Examples include naloxone (Narcan; mu-opoid receptor blocker) for opiate overdose

Aversive Treatment

Drugs that make the ingestion of abused substances extremely unpleasant Examples include Antabuse for alcoholism and silver acetate/nitrate for nicotine addiction. Make the experience so unpleasant that it reduces use. Learned associations to disrupt the rewarding experience of ingesting drugs.

Depression

Falls in the umbrella of mood disorders. The most prevalent of the mood disorders. Unhappy mood, loss of interest, low energy and appetite, difficulty concentrating, restless agitation. Depression affects how a person feels, thinks and behaves. Periods of depression can occur spontaneously and persist for months on end if not treated. Clinically significant; can be deadly. Very common; estimated to affect up to 20% of the population at one time. Not just a state of mind; associated with changes in brain structure and function.

Deep Brain Stimulation

For patients who don't respond to therapeutics of ECT. Being explored in clinical trials. Involves delivering mild electrical stimulation, typically of a region called the sub-callosal cingulate (under the corpus callosum in PFC). DBS involves implanting an electrode in the area of the brain, delivering some stimulation, and in doing so yields clinically significant improvements in mood that happen instantaneously.

HPA in Depression

High levels of circulating glucocorticoids may cause depression. Stress activates the HPA axis. Results in the paraventricular nucleus of the thalamus secreting corticotropin releasing hormone (CRH) which causes the anterior lobe of the pituitary gland to secrete adrenocorticotropic hormone (ACTH) which results in the increase of glucocorticoids like cortisol being released by the adrenal gland. Overactive stress response leads to more CRH. High levels of CRH decrease serotonin receptors in the hippocampus. Proposed to reduce hippocampal inhibition of the HPA; leads to a failure to reduce the activation of the circuit. In healthy individuals, there is usually a negative feedback that involves cortisol's action on the hippocampus and subsequently the hippocampus's actions on the hypothalamus which reduces activation PVN which functions to release CRH. Via reduction in serotonin receptors in the hippocampus, this feedback loop is dysfunctional.

Animal Models of Depression

In learned helplessness, an animal is exposed to a repetitive stressful stimulus and subsequently experiences behavioral changes also seen in depression. Learned helplessness is linked to a decrease in serotonin function and dopamine. Takes no action in response to aversive stimulus. Removal of olfactory bulb creates a model of depression in animals reversed by many antidepressants.

Psychiatric Conditions

Involve an imbalance in brain chemistry. There is dysfunction in one or more NT systems that drugs can be used to fix.

Cell to Cell Interactions

Involve the translation of electrical --> chemical --> electrical signals. Inter = chemical, intra = electrical. Many drugs function by affecting aspect of chemical transmission

Monoamine Oxidase Inhibitors (MAOIs)

Monoamine NTs. Increases the levels of monoamines at the synapse; inhibiting the enzyme that is breaking down the NT. Suggests that depressed people do not get enough stimulation at those synapses. Effective in reducing the symptoms of depression led to the monoamine hypothesis. Monoamines include serotonin, dopamine, and norepinephrine. Have caveats: an association with significant withdrawal symptoms, can be severe if it is discontinued abruptly, needs to be tapered. Don't alter the course of the disease; possible that when a patient stops taking the drugs, the discontinuation can return the patient to a pre-treatment state. First class of drugs to treat depression; first generation.

Treatments for Depression

Monoamine oxidase inhibitors (MAOIs), tricyclics, selective serotonin reuptake inhibitors (SSRIs), electroconvulsive therapy (ECT), deep brain stimulation (DBS), transcranial magnetic stimulation (TMS), and cognitive behavioral therapy (CBT)

Systems Disrupted in Depression

Monoamines are reduced in depression: serotonin, dopamine (overwhelming number of Parkinson's patients suffer depression), norepinephrine (may contribute to social dysfunction) --> decreased alertness, energy, cognitive ability that plays a determinant role in cognition and motivation. GABA is reduced in the CSF of the anterior cingulate cortex. Many of these findings are corroborated in animal models of depression.

Functional Brain Changes with Depression

PET scans in depressed individuals show there are increases in metabolic activity in the prefrontal cortex and amygdala, however, there are decreases in activity in the posterior parietal lobe, posterior temporal lobe, and anterior cingulate cortex. fMRI imaging in depressed individuals shows that amygdala activity is stimulus dependent: hypoactive to happy faces and hyperactive to sad faces. Psychiatric disorders are heterogenous and complex. Whether there is increased or decreased activity doesn't matter; it's still aberrant activity and responses to stimuli are maladaptive.

Drug Effects

Produce agonistic and antagonistic effects. This depends not only on the drug but also on the receptor that it is interacting with. Repeated exposure alters the structure and function of the synapse, cells, and brain. Alterations in structure and function contribute to potentially tolerance or sensitization to those compounds. Tolerance relates to withdrawal; sensitization relates to overdose

Agonist Substitution

Safer drug with a similar chemical composition as the abused drug. Examples include methadone for heroin addiction

Issues with SSRIs

There are issues with the theory that reduced serotonin is causal for depression. Know that SSRIs increase the amount of serotonin at synapses within hours of administration, but it typically takes several weeks of SSRI treatment before patients report feeling better. Paradox suggests that it is the brain's response to increased serotonin, not serotonin itself, that relieves symptoms of depression, which takes time. SSRIs don't help everybody. In a study looking at effectiveness of SRRIs about 1/3 of patients taking a placebo reported feeling better. This could indicate that for some people, taking any antidepressant drug will improve symptoms. SSRIs only reduce effects of depression in individuals who are the most depressed. For patients with mild to moderate depression, SSRIs and placebo were just as effective in reducing symptoms of depression. 20% of individuals who take SSRIs show no improvement at all. SSRIs can increase the rate of suicide in children and adolescents. Too high of a dose can lead to serotonin syndrome which can be lethal.