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1 Southern Medical Association July 2011 Robert A. Bashford, M.D., Professor Associate Dean for Admissions University of North Carolina Professor of Psychiatry and OB-GYN!" #! $ %&'(%&) $ * &+ %&, ' ) # * %, # -./ 01/ /7 23 #, 2 3 1

2 Serotonergic Projections Mediate: Appetite Sleep Anxiety Fear Aggression Sexual Behavior Pain Risk Factors For Depression Prior episodes of depression Family history of depression Prior suicide attempts Female gender Age under 40 Postpartum period Medical comorbidity Lack of social support Stressful life events Current substance abuse? ART Mood Disorders Bipolar Affective Disorder Mood Disorder Secondary to medical condition Substance Induced Mood Disorder Dysthymia Premenopausal Dysphoric Disorder Major Depressive Disorder Major Depressive Disorder Post-Partum Depression Postpartum Depression SAD-A-FACES $leep $$ Insomnia or hypersomnia +ppetite or weight change ysphoria ( Bad bad mood Mood - irritable or sad) +nhedonia (Lack of interest or pleasure) 8atigue +gitation %oncentration diminished 9steem low self esteem or guilt $uicide $$ or thoughts of death 2

3 Why Treatment? Marriage Misery Safety Kindling Infant (Intrapartum and postpartum) Safety (Rule of Sevens) 1 of 7 with recurrent depressive illness commit suicide 70% of suicides have depressive illness 70% of suicides have seen their primary care doctor within 6 weeks of suicide Suicide is 7 th leading cause of death in U.S. Safety includes substance abuse, poor nutrition, and care with pregnancy Why Treatment? Marriage Misery Safety Kindling Infant (Intrapartum and postpartum) Kindling Repeated sub-threshold stimulus of neuron eventually generates an action potential Mood disorders may involve kindling in the temporal lobe General Guidelines After Diagnosis Adequate Dose - Adequate Time Psychotherapy Side Effects Previous Response/Family History Educate Educate Safety Safety Rule Out Before Treatment Safety Substance Psychosis Violence Adjustment Mania or Hypomania Mania or Hypomania Atypical Personality Disorder Personality Disorder 3

4 Mania or Hypomania Early onset of a mood disorder More mood lability and anger Interpersonal difficulty Legal impulsive spending, sex, or job difficulty Family history Atypical Depression Increased weight and appetite Leaden paralysis Increased sleep Long-standing rejection sensitivity Difficult to treat Personality Disorder Enduring affective and behavioral disturbance Early onset (18) Pervasive and stable with resultant unhappiness and impairment Who Treats? 15-20% of depressions are correctly diagnosed and treated. 70% are treated by a primary care physician. :%+;<9=9$$+;=><,+9 %;%9<; 65/? 1-/ Mechanisms of Action: Antidepressants Tricyclic antidepressants (TCAs) predominantly inhibit norepinephrine reuptake Serotonin reuptake inhibitors (SSRIs) predominantly inhibit serotonin reuptake. Medications inhibiting 5-HT are often more effective in anxiety disorders than those inhibiting NE SSRI selectivity for 5-HT is associated with a lesser potency in down-regulating adrenergic receptors with chronic treatment, which can weaken antidepressant effects (i.e., tolerance) 5 HTTLPR gene (1 o therapeutic target) 4

5 Side Effects of SSRI s Nausea Stimulation Sedation Apathy/cognitive dysfunction Withdrawal Sexual Sexual Weight gain Weight Gain Recent Medical Complications Bleeding risk Hyponatremia Gynecomastia Increased lipid and cholesterol Osteoporosis Serotonin toxicity Reproductive effects Primary Psychiatry February 2008 Vol. 15 Weight Gain Remeron Paxil Zoloft Prozac Effexor Wellbutrin Star*D Multisite Study Multisite trial for treatment of resistant depression 10/99 funded by NIMH 5,000 self-declared patients» 60% specialty clinic» 40% primary care clinic Real life patients with medical and psychiatric comorbidities Star*D Lessons Learned Aggressive dosing Medication changes earlier rather than later Major depressive disorder looks the same in primary care and specialty clinics Medication changes as early as 2-4 wks if intolerable side effects or no improvement Major depression with significant anxiety symptoms more resistant to treatment and may require additional medications Treat to wellness More effective antidepressants (Effexor)??? Impact of side effect Impact of substance and medical comorbidities yet to be understood 5

6 STAR*D Child Study One Year After Remission of Maternal Depression Major depression and anxiety disorders significantly increased in the offspring of parents with major depression Children s symptoms and problem behaviors decreased in the one year following maternal remission of symptoms This does not vary with the length of time to maternal remission (???) No conclusions yet whether treating depressed parents benefits children or children s better outcomes contributes to mother s remission of depression Effects of treating depressed fathers next (Lancet 05 reports 2X risk of behavioral and emotional problems in children 3.5 years old) Intra- & Post-Partum Anxiety-like disorder Symptoms camouflaged by pregnancy but anhedonia, suicidal ideation, guilt (extreme vigilance) are markers FDA not helpful Treat in first trimester? Mom s depression affects children Ambiguous Symptoms of Depression in the Postpartum Period Appetite or weight changes Sleep difficulties Fatigue Psychomotor retardation or agitation Diminished subjective perception of ability to think or concentrate Libido Non-Ambiguous Symptoms of Depression in the Postpartum Period Guilt and decreased self-esteem Anhedonia Suicidal ideation Marked vigilance Edinburgh Postnatal Depression Scale EPDS scores over 12 identified as women with possible major depression Edinburgh Postnatal Depression Scale detects but does not distinguish anxiety disorders from depression May over report minor depression or adjustment disorder ACOG strongly encourages but does not mandate screening for perinatal depression 6

7 Risk Benefit for Treatment in Pregnancy FDA reductionistic and not helpful Perceived warning as optimal approach Buproprion FDA B C - human data lacking animal data positive (with huge doses) or not done Paxil as a teratogen (cardiac) Consequence of no treatment is an integral part of the discussion SSRI Exposure and Adverse Outcome 15 to 30% experience tachypnea, hypoglycemia, temperture instability, irritability, weak cry, and possibly seizures Is this withdrawal syndrome or discontinuation syndrome? Potential Risks of Not Treating with Psychiatric Medications Depression may be associated with poor obstetric outcomes (preeclampsia, preterm delivery, low birth weight, miscarriage, small for dates babies, neonatal complications (high cortisol levels at birth?) Children of depressed mothers have more medical, psychological, and cognitive problems Increased risk of recurrence and treatment resistance of illness Review Psychiatric Neuroscience 2008; 33(4) Fetal Toxicity of SSRI s and Tricyclics Intrauterine death» No increased risk Physical malformation» No increased risk Paxil (????) Growth impairment» One Fluoxetine study with significantly lower birth rate after 25 weeks gestation -????? Behavioral Teratogenicity» Only 1 study with no change in cognitive function, temperament, or general behavior in exposed children Neonatal Toxicity» Questionable poor neonatal adaptation with hypotonia and difficulty regulating temperature and sleep/wake cycles ;9;++A+!$<;9;%9 $B;=,9 Abnormal sleep, motor ability, heart rate 9=$<$9;"A,;+=B&B9=9;$<; 44@C?D$$=< 15 ='?(1:?555) $7!,< %( 30% (13% severe) on SSRIs Arch Ped & Adol Med, Feb 06 7

8 Serotonin Seclective Re-uptake Inhibitors Treatment Therapeutic effects evident for fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), and venlafaxine (Effexor) Sertraline has the lowest breast milk exposure All of the SSRIs have been approved for treatment of one or more anxiety disorders Anxiety symptoms are prominent in perinatal depression The seclection of an individual SSRI or SNRI is inconclusive (excluding paroxetine [Paxil]) Insomnia Severity Index (ISI) Predicts a Positive Edinburgh Scale Age Difficulty falling asleep Difficulty staying asleep Early awakening Dissatisfaction with sleep pattern Daytime functioning impaired Impairment noticeable to others Distress about sleep problem Treatment of Insomnia Benzodiazepines (Ativan, Klonopin) Selective Benzodiazepine Agonist (Ambien, Sonata) Now-Benzodiazepines (Lunesta, Ambien) Sedating Antidepressants (Trazadone, Remeron) Sedating Antihistamines (Benadryl, Atarax) Atypical Antipsychotics (Seroquel) Natural Compounds (Melatonin) Benzodiazepine Anxiolytics/anticonvulsants Sedatives/muscle relaxants Begin with low dose, high potency, longer acting benzos such as Klonopin (Clonazepam) XR Xanax Always have plan for discontinuation Potential Side Effects of Benzodiazepine Discontinuation Syndrome Tolerance/dependence Cognitive blunting Sedation Amnesia Transdermal Estradiol for Post Partum Depression Studies suggest depression threshold lowered with drop in gonadal steriods 2-5 X increase in psychiatric hospitalizations in post partum depression 2-3 X increase in major depression in the perimenopause 17 beta estradiol is most physiologic estrogen The lack RCTs; side effects; and possibly the women s health initiative study have all put the use of estradiol on hold 8

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