S

Psychopharmachology

Lecture 3 – Depression and Anti-Depressents

Mental health for all by involving all

Nearly 450 million people are affected by mental.

In wealthy nations, just half receive appropriate care, but in developing countries, close to 90 percent go untreated because psychiatrists are in such short supply.

Vikram Patel outlines a highly promising approach -- training members of communities to give mental health interventions, empowering ordinary people to care for others.

Vikram Patel helps bring better mental health care to low-resource communities -- by teaching ordinary people to deliver basic psychiatric services worldwide

http://www.ted.com/talks/vikram_patel_mental_health_for_all_by_involving_all.html

Pharmacokenetics and Pharmacodynamics

Pharmacokenetics– What the body does to the drug.

Pharmacodynamics – What the drug does to the body.

Pharmacokenetics - ADME

Absorbtion (A) – How the body takes in the drug (stomach, lungs, patches, intestines).

Distribution (D) – How the body is transported through out the body.

Metabolism (M) – How the body transforms the medication and for many psychiatric medicaitons this occures in the liver.

Excretion (E) – How the body eleminates the medication.

Autonomic Nervous SystemStress Response

Depression – Health Crisis

17% of people in the America will have symptoms of depression at some point in their life.

Depression is not a mental health issue it is a health issue.

From the WHO: Globally, more than 350 million people of all ages suffer

from depression.

Depression is the leading cause of disability worldwide, and is a major contributor to the global burden of disease.

Depression Overview

Neurotransmitters in Depression

Norepinephrin – Effects behavioral activation, arousal and mental filter aspect of attention. Absence leads to lethargy poor attentional control.

Dopamine – Pleasure, desire and motivation. Low levels of dopamine lead to anhedonic symptoms.

Seratonin – Satiation, here and now happiness, and absence is guilt and worry.

Serotonin Genes & Depression

Serotonin Genes & Depression

Depression Overview Cortisol Hypothesis

Many individuals with depresion display hypercortisolism (Elevated Cortisol – A.K.A. Stress Hormone).

High levels of Cortisol drives down Dopamine levels.

People with chronicly high cortisol have symptoms of depression. Consider Cuishings Disease.

Depression Overview Cortisol Hypothesis

Elevated Cortisol – Leads to hipocampal atrophy similar to the atrophy found in individuals with depression.

Adverse Childhood Events – Leads to increased risk for depression and changes life-toime levels of Cortisol.

In some studies of Anti-depressent treatment those who’s Cortisol was reduced showed low to zero remission rates where those with out this fact had high rates of relapse.

Stress and Neurons

Epigenetic Mechanisms

Autonomic Nervious System

Stress Reactions

Tracking the Stress Response

Depression Overview Hormones

Changes in hormones effect depression. Changes in cortisol change mutliple hormones

Post-pardum depression is common. Blues are highly common and one needs to differentiate between depression. Most of the time, it occurs within the first 3 months after delivery.

Triggers: Changes in your body from pregnancy and delivery, Changes in work and social relationships, Having less time and freedom for yourself, Lack of sleep, Worries about your ability as a mother.

Up-to-date information about medication use during lactation is available on TOXNET lactmed at http://toxnet.nlm.nih.gov

Menipause is a common trigger for depression.

Premenstrual dysphoric disorder (PMDD) – Harmone therapy (severe cases), Estrogen replacement, and anti-depresent (SSRI/SNRI).

Clinical Discussion

Depression Overview

Neuroplastic Hypothesis:

BDNF (Brain derived neurotrophic factors) – Involved in health of the brain tissue and rates of neuroplasticity. Involvoed in “Metaplastic” brain activity.

If this factor is blocked during treatment by SSRI the anti-depressent has little to no effect.

Studies are mixed about its direct anti-depressent effects.

Exercise increases rates of BDNF secreation and may underly the increased neurogenisis and dendritic arboring from exercise.

Depression OverviewInflamation Hypthesis

Inflamitory response is involved in the bodies immune function.

Inflation is elevated in many chronic diseases such as heart disease, arthrhitis, pain syndroms and depression. It may be an underlying stressor leading to neurodegenerative diseases.

Inflamtion is increased by hypercortisolism and can be effected by diet.

Some common medications have been tested to treat depression. One study found treatment resistant depression was treated well but only in those with a high amount of inflamation markers.

One study found increased efficacy of SNRI’s for heart conditions possibly mediated by effects on inflmation response. DOI: 10.1016/j.ijcard.2008.02.013

Biological Treatments of Depression

MAO-I: First anti-depresents. Rarely used Due to lethal effects. Work to inhance dopamine, norepinephrine and serotonin.

Selegiline a MAO-I b Medication: Was approved in 2006 for depression and is intrials for ADHD. Also used in Parkinson’s treatment.

It works on MAO-b which is more selective for dopamine and does not have the Tyrimine effects.

Biological Ethnopharmachology

The J mutation of the CYP 2D6 is found in 47% to 70% of Asian Americans.

Z mutation is found in 15% to 20% of non-Hispanic African Americans and is responcible for CYP 2D6 and slows down metabolisim of antibiotics, cardivascular drugs, pain medication and antidepresents.

When considering prescription and dossages of SSRI’s for African Americans of non-hispanic descent, Puerto Rican and Dominican adolescents one needs to take these metabolic factors into account.

Biological Treatments of Depression

Trycyclics: Second generation anti-depressent medications. These medications effect serotonin and norepinephrine. They have limited to no effect on dopamine.

SSRI: Are focused at the reuptake process and specifically serotonin. They treat anxiety and are used as adjunt treatment in multiple health and mental health dissorders (1–4 weeks while the body adapts to the drug and 6 to 8 weeks to full effect).

SNRI: Are focused on the reuptake of serotonin and norepiniphrine. They can be activating.

Welbutrin: Works on dopamine and norepinephrine. Is activating, is used to treat smoking and or weight loss. A common of lable use is the treatment of ADHD.

SSRI Side Effects - 2005 Harvard Mental Health

Letter Physical symptoms: Some patients taking SSRIs develop insomnia,

rashes, headaches, joint and muscle pain, stomach upset, nausea, or diarrhea. These problems are usually temporary, mild, or both.

Bleeding problems: A more serious potential problem is reduced blood clotting capacity that increases risk for stomach or uterine bleeding, if patients use SSRIs and NSAIDs (aspirin, ibuprofen, naproxen, COX-2 inhibitors).

Sexual effects: For many patients, SSRIs diminish sexual interest, desire, performance, satisfaction, or all four. (Viagra) can help.

Suicide: The risk that antidepressants will incite violent or self-destructive behavior. When compared with a placebo, all antidepressants, including SSRIs, seem to double the risk of suicidal thinking, from 1%–2% to 2%–4%, in both children and adults.

SNRI Side Effects

Similar to SSRI.

Tend to be more stimulating due to norepinephrine component.

At times associated with anxiety, elevated pulse and blood pressure.

Sexual dysfunction: Lack of interest in sex and difficulty reaching climax (anorgasmia).

Nausia is reduced in extended release formulation.

Biological Treatments of Depression

Psychostimulents: Focus on changing dopamine and increase beahvioral activation but also at times can lead to disinhabition and loss of appitite. Effective short-term significant reduction in symptoms but clinical significance is less clear.

NRI (Norepinephrine Reuptake Inhibitors) – Straterra ADHD limited to no effects for depression in double blind studies.

NDRI (Norepinephrine Dopamine Reuptake Inhibitors) - Wellbutrin, Zyban.

Role Play

Biological Treatments of Depression

Deep Brain Stimulation: An electrode is implanted in the subcallosal cingulate and continuously stimulated. Effctive in refractory depression and as a treatment for parkinsons disease. Video

ECT: Is used often to treat refractory depression. Unipolar is less damaging. It can cause memory loss that mostly remits after four weeks. Very few placebo control studies. A trial of CBT or other psychotherapy is not included in criteria for “treatment resistant depression.”

Biological Treatments of Depression

Ketamine: New drug target. Rapid symptom change (1 hour). Adaptation from street drug “special K” caused holucinations.

Inflamation Drug Tragets TNF-Alpha (Infliximab): Some indications of efficacy

in treatment resistant depression. Celecoxib – Effective in a 2006 placibo controled

piolet study.

Biological Treatments of Depression

Cortisol: Several drug targets have the effects of blocking cortisol. These medications have limited effects on treatment of depression but in at least one trail treated psychosis associated with depression and halucinations.

TMS (Transcrainial Magnetic Stimulation): Sends a burst of magnetic energy across the skull and stimulates an area of the brain. Has shown effects in refractory depression in a placebo control study. (Left dorsolateral prefrontal cortex)

Vagal Nerve Stimulation: Stimulates the vagus nerve (parasympathetic – relaxation response) and has been found to have some effects in moderate refractory depression.

PsychologicalTreatments of Depression

Interpersona Therapy (ITP) – An evidence based treatment. Holds that there are three areas of life disrupted in depression. Personality, Social Functioning and Symptoms. Treatment focuses on social functioning and pragmatic solutions to symptoms.

Cognitve Behavioral Therapy (CBT): Addresses thoughts and cognitions as well as behaviors that maintain symptoms. It focuses on changing schema’s about the self, world and future.

Behavioal Therapy – Based on learned helplessness. Behavioral theory holds that there is a lack of behaviors. This lack of behaviors leads to lower levels of reinforcers. Lower reinforcers leads to increased depression. Increase behavioral activation leads to reduction of symptoms of depression.

Psychobiological Treatments

Massage and body work: Solid studies exploring this modality have found good symptom reduction.

Yoga Nidra: Preliminary data has found solid efficacy for treatment of depression. Further Readin, “Yoga For Depression.”

MBSR: Some indications of efficacy for depression treatment (e.g. depression post-cancer dx). Mix results in some studies. Particular reduction in rumination.

Additive Risk: Genetic, Early Life Stress & Relationships

Early Life Stress – Increases risk of depression.

Serotonin Genetics – Increased risk of depression significantly above and adding to early life stress (Short-Short worst combination, Long-Long best).

Poor social relationships increases in a synergistic way risk of depression more then double those with poor social relationships.

Clinical Case Discussion

Closing Questions

???