Depression DSM-IV diagnoses –Major depression Symptoms of major depressive disorder common to adults, children, and adolescents Persistent sad or irritable mood* Loss of interest in activities once enjoyed* Significant change in appetite or body weight Difficulty sleeping or oversleeping Psychomotor agitation or retardation Loss of energy Feelings of worthlessness or inappropriate guilt Difficulty concentrating Recurrent thoughts of death or suicide Five or more of these symptoms must persist for 2 or more weeks before a diagnosis of major depression is indicated.
Risk Factors for Major Depression Female gender Family history of depression Limited social support Separation/Divorce Early parental death Negative life events Post-partum
Pharmacologic Agents that Can Cause Depression Alcohol Analgesics (e.g., codeine) Sedative-hypnotics Anxiolytics Steroids Oral Contraceptives Antihistamines (with long-term use) Chemotherapy medications
Pharmacologic Agents that Can Cause Depression Cardiac medications (antihypertensives) Anticholinergics (antispasmodics) Amphetamines Cocaine Cannabis Hallucinogens
Medical Disorders that Can Cause Depression Addison’s disease Infectious hepatitis AIDS Influenza Anemia Malignancies (cancer) Asthma` Malnutrition Chronic Fatigue Syndrome Multiple sclerosis Chronic infection (mononucleosis, Rheumatoid arthritis tuberculosis) Syphilis Chronic pain Systemic lupus erythematosus Congestive heart failure Ulcerative colitis Cushing’s disease Uremia Diabetes Hypothyroidism
A Little Epidemiology 5-11% lifetime prevalence 10-14 million in U.S. depressed 50% recurrence following 1 st episode, higher if multiple episodes (70-90%) 15% complete suicide ultimately
Episodic with untreated episodes lasting 6-24 months Longitudinal course of depression
Double depression is a syndrome characterized by transitions between episodes of major depression and dysthymia
Treatment with medication results in a “response” (50% or greater improvement) in 67% of patients
Depressed patients who respond will experience a recurrence rate 50% if med is stopped and placebo substituted
Depressed patients who respond will experience a recurrence Rate of 10-15% if their medication is continued for one year following recovery
Etiology of Depression Psychological factors – Reduced reinforcement Few available potentially reinforcing events related to personal characteristics Little available reinforcement in the environment Few effective behaviors and skills available
Etiology of Depression Cognitive factors/dysfunctional thinking – Negative views of self, world, and future –Negative cognitive filter distorts perceptions
Etiology of Depression Learned helplessness – Failure to learn mastery of environment – Depressed have learned that their response, or lack of response, doesn’t change anything – History of inability to control or influence negative events
Genetics in Mood Disorders Best evidence is for bipolar disorder with first degree relatives. Twenty-four times more likely to develop disorder. Relatives of depressed have 2 to 5 times greater risk for depression Concordance rate for bipolar disorder in MZ twins is 79% and for DZ twins is 19%
Neurotransmitter—Receptor Hypothesis Monoamine hypothesis – activity of 5HT, NE, DA in the CNS –All anti-depressants affect availability of monoamines in synapses –Monoamine irregularities are widely reported in depressed 5HT and 5HT 2 binding sites in post mortem brains of suicide victim 5HT 2 binding sites in the platelets of depressed
Neurotransmitter—Receptor Hypothesis Monoamine hypothesis –Monoamine irregularities are widely reported in depressed 5-HIAA CSF levels in depressed who attempt suicide PCPA, which decreases 5HT synthesis, reverses clinical efficacy of anti-depressants Beta-adrenergic and alpha-2 adrenergic receptors in post mortem brains of suicide victims 5HT and NE autoreceptors reduces 5HT and NE output
Interactional Neurotransmitters Hypothesis Single NT theory does not suffice Two or more NT systems have modulatory interactions Decreased 5HT and decreased NE subserve depression Decreased 5HT and increased NE subserve mania Cholinergic activity > NE activity may play role in depression Cholinergic activity < NE activity may play role in mania
Role of NE, 5HT and DA in the Generation of Depressive Symptoms Anxiety Irritability Energy Interest Motivation Mood, Emotion, Cognitive Function Sex Appetite Aggression Norepinephrine Serotonin Impulse Drive Dopamine
Bio-Rhythm Hypothesis Desynchronization of circadian rhythms in depression Anti-depressants alter these rhythms Disturbances in sleep/wake cycle are hallmark of depression –Non-REM changes total sleep sleep onset latency
Bio-Rhythm Hypothesis –Non-REM changes arousal threshold wakefulness Early a.m. awakening –REM changes in REM onset latency in REM density Redistribution of REM sleep to earlier
Neuroendocrine Hypothesis Cortisol hypersecretion, blunted growth hormone and prolactin responses, blunted TSH response to TRH, reduced lutenizing hormone secretion all have been associated with depression Dysregulation of the H-P-A axis results in cortisol and abnormal daily rhythms of cortisol levels
Neuroendocrine Hypothesis Dexamethasone suppression test does not suppress cortisol in 50% of depressed Dysregulation of the H-P-T axis creates thyroid hormone deficiencies which may be found in depression Severe early childhood trauma may affect HPA functions and lead to vulnerability to develop depression when facing stress later
Neuroendocrine Hypothesis Hormonal changes in women may be related to higher rates of depression –Postpartum depression –Menopausal depression –Pre-menstrual distress –Oral contraceptives may cause depression
Seasonal Affective Disorder (SAD) First described in 1984 Subtype of major depression characterized by onset at a certain time of the year, usually winter. A specifier that can be applied to major depressive episodes in Bipolar Disorder and Major Depression, Recurrent
DSM IV Requires that 4 Criteria be Met in Order to Use the SAD Specifier A regular temporal relationship between onset of major depressive episodes and a particular time of the year (e.g. September – October). Should not include cases in which there is a regular seasonal stressor such as unemployment during the winter. Full remissions also occur at a characteristic time of the year (e.g. March-April).
In the last 2 years, 2 depressive episodes have occurred that demonstrate the seasonal relationship. Seasonal depressions substantially outnumber non-seasonal depressions that may have occurred over the individual’s lifetime DSM IV Requires that 4 Criteria be Met in Order to Use the SAD Specifier
Symptoms of Depression in SAD SAD patients have the usual symptoms of depression such as sad mood, reduced interest, decreased concentration, low energy and fatigue. SAD patients also tend to have “atypical” symptoms of depression such as increased sleep, increased appetite, weight gain, and carbohydrate or sweets craving.
Epidemiology Prevalence estimates are 1-4% in the U.S., 2-3% in Canada, 1-3% in Europe, and 0-.9% in Asia. Female to male ratio is about 2:1 as is the case with major depression. Lifetime prevalence increases with age until the 6th decade at which point the prevalence declines sharply. SAD prevalence in over 65 years is very low. Mixed results in prevalence with respect to SAD and latitude. Recent studies using better diagnostic tools suggest the latitude effect may not be as strong as previously thought.
Differential Diagnoses Seasonally recurrent psychosocial stressors such as winter unemployment, anniversary grief reactions during winter. Other conditions may vary with season such as eating disorders, premenstrual syndromes, and anxiety disorders. Some people notice marked changes in sleep, appetite, and energy during the winter but don’t meet criteria for major depression.
SAD Light Treatment Daily scheduled exposure to bright artificial light Exposure to 10,000 lux for 30 minutes daily = 2,500 lux for 2 hours Exposure is most effective in the early morning upon awakening Response rate is 65% in 2-3 weeks Side effects include eye strain, headaches, feeling wired, nausea, sweating
SAD Medication Treatment Best evidence involves SSRIs Response rate is about 60% Combo SSRI and light for more severe depressions
Recommended Steps When Primary Care Physicians Encounter Patients with Clinical Profiles Suggesting Depression Screen for Depressive Symptoms Screen for General Medical Conditions or Linkages to Substances or Medications Known to Cause Depression Establish Dx of MDD and Determine Mood Subtype A) Unipolar B) Bipolar C) “Atypical” D) Seasonal Affective Disorder E) Comorbid Depression Anxiety/Panic OCD Anorexia/Bulimia Alcoholism F) Psychotic Depression Maintenance Treatment when Indicated Management of Side Effects, Augmenting Agents,and/or Second Line Treatments if Necessary Depending on Subtype, Treat Acute Episode with “First Line” Treatments, Emphasizing Adequate Duration and Dosage
Use of Antidepressants in Primary Care 1st line –SSRIs (Prozac, Zoloft, Paxil, Celexa, Lexapro) –Venlafaxine (Effexor XR) –Bupropion (Wellbutrin) 2nd line –Duloxetine (Cymbalta) 3rd line –Tricylics, Mirtazapine (Remeron) 4th line –Monoamine oxidase inhibitors (MAOIs)
Selecting Antidepressants Antidepressants not commonly associated with weight gain –Wellbutrin –Effexor –SSRIs (Paxil?) –Cymbalta Antidepressants not commonly associated with sexual side effects –Wellbutrin –Celexa –Remeron
Pharmacotherapy of Depression Overall antidepressant response rates are similar for antidepressants Remission rates, however, are higher in severe depression for dual action 5HT + NE antidepressants than for SSRIs Patients may have better results with one antidepressant than another Remission is the goal of antidepressant treatment, no matter what antidepressants or combination is prescribed