Kerry Pierce MD Board Certified Adult and Geriatric

Kerry Pierce, MD Board Certified Adult and Geriatric Psychiatry Mid. Michigan Physicians Group

Major Depression, Seasonal Depression, Winter Blahs

Major Depressive Disorder

Depression: Emotional and Physical Signs Emotional Physical Hopelessness Fatigue Low self-esteem Vague abdominal pain Impaired memory Difficulty concentrating Vague joint pain Headache Disturbed sleep Anhedonia Sexual dysfunction/apathy Anxiety “Stressed out” Preoccupation with negative thoughts GI complaints (constipation, diarrhea…) 4

Epidemiology of Depression Lifetime prevalence of a major depressive episode (MDE): 17% – Male: 13% – Female: 21% – 16 million adults currently with MDD (2016) Trends – Age at onset: – Incidence: – Etiology: younger increasing biologic vs psychological 5

Medical Conditions Associated With Depressive Symptoms • Cardiovascular disease 60% of post MI • Endocrine disorders – thyroid, menopausal… • Rheumatoid arthritis • Brain trauma, tumors • Vitamin B 12 deficiency – after gastric bypass, alcoholism… • Parkinson’s disease – 50% • Viral infections (e. g. , • Irritable bowel syndrome influenza, HIV) • Fibromyalgia • Cancers

Consequences of Untreated Depression • Prolonged and increased suffering • Poorer quality of life • Poorer physical, social, and role functioning – decreased productivity (absenteeism, presenteeism) • Increased use of healthcare resources • Increased morbidity, mortality in other medical illnesses • Psychiatric or medical hospital admissions • Suicide

Depression May Worsen Outcome of General Medical Conditions • Depression may worsen morbidity and mortality after myocardial infarction 1, 2 and in patients with CHF 3, 4 • Depression increases risk of mortality in patients in nursing homes 5 • Depression worsens morbidity post-stroke 6 • Depression may worsen outcomes of cancer, diabetes, AIDS, and other disorders 7 1. Frasure-Smith N, et al. JAMA. 1993; 270: 1819 -1825. 2. Penninx BW, et al. Arch Gen Psychiatry. 2001; 58: 221 -227. 3. Jiang W, et al. Arch Intern Med. 2001; 161: 1849 -18 4. Vaccarino V, et al. J Am Coll Cardiol. 2001; 38: 199 -20 5. Rovner BW, et al. JAMA. 1991; 265: 993 -996. 6. Pohjasvaara T, et al. Eur J Neurol. 2001; 8: 315 -319. 7. Petitto JM, Evans DL. Depress Anxiety. 1998; 8(suppl 1): 80 -84.

Remission Relapse Euthymia Syndrome Recurrence + Response on ssi gre r Pro rde iso Symptoms Relapse d to Increased severity Remission Is the Goal of Treatment in Major Depression Treatment phases + Acute (6 to 12 wk) Continuation Maintenance (4 to 9 mo) ( 1 y) Time Adapted from: Kupfer DJ. J Clin Psychiatry. 1991; 52(suppl 5): 28 -34.

Recurrence Becomes More Likely With Each Episode of Depression First episode <50% ≈70% Second episode >90% Third + episode 0 20 40 60 80 % of patients expected to experience recurrence Stahl SM. Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 2 nd ed. Cambridge, UK: Cambridge University Press; 2000: 150. 100

Major Depression Common Treatment Options ANTIDEPRESSANT MEDICATIONS MAOIs – Nardil, Parnate, Selegiline Tricyclics – Elavil, Pamelor, Tofranil, Norpramin, Doxepin SRIs – Prozac, Zoloft, Paxil, Luvox, Celexa, Lexapro Dual action – Effexor, Pristiq, Wellbutrin, Remeron, Serzone, Cymbalta, Viibryd, Fetzima, Trintellix Misc. – mood stabilizers, stimulants, atypical antipsychotics, thyroid, ketamine? Psychotherapy - Cognitive behavioral, Interpersonal Medication + Psychotherapy = optimal outcome Electroconvulsive Treatment (ECT) - 1938 Bright Light Therapy – 1984, not just for SAD Vagal Nerve Stimulation (VNS) - 2005 Transcranial Magnetic Stimulation (TMS) - 2008

The Evolution Of Antidepressants 1950 s 1970 s 1960 s Phenelzine Maprotiline Isocarboxazid Amoxapine Tranylcypromine Doxepin Imipramine Clomipramine Nortriptyline Amitriptyline Desipramine 1980 s 1990 s >2000 Fluoxetine Sertraline Duloxetine Paroxetine Desvenlafaxine Fluvoxamine Vilazodone Citalopram Levomilnacipran Vortioxetine Nefazodone Mirtazapine Venlafaxine Escitalopram

Likelihood of Discontinuing Treatment Increases With Each New Medication Attempt Systemic Drug Side Effects q Weight Gain q Fatigue q Constipation q Headache/ q Diarrhea q Nausea Migraine q Abnormal Ejaculation q Drowsiness q Impotence q Insomnia q Sweating q Decreased Libido q Tremor q Nervous Anxiety q Treatment q Increased Appetite q Decreased Appetite Discontinuation Side Effects q Weakness q Dry Mouth q Dizziness 13 Trivedi (2006) Am J Psychiatry; Rush (2006) Am J Psychiatry; Fava (2006) Am J Psychiatry; Mc. Grath (2006) Am J Psychiatry; Neuronetics, Inc. (data on file)

Psychotherapy • Cognitive Behavioral (CBT) – examination of ones thoughts (cognitions) in relation to situation to eliminate ANTs (automatic negative thoughts) • CBT + medications or phototherapy shown to be beneficial in acute MD and SAD episodes and to prevent or diminish future episodes • Mindfulness Meditation – moment to moment awareness of what is going on within and around you, sadness is part of daily emotional spectrum • Transcendental Meditation – use of a mantra to attain clarity of mind (transcend time and space)

MDD Treatment Algorithm 10 M Primary Care Psychiatry • Initial Diagnosis • Early Treatment Attempts • • Number of MDD Patients 8 M Improved Diagnosis Improved Dosing Psychotherapy New Treatment Options 6 M 4 M 2 M SSRI Combination & Augmentation – Atypical Antipsychotics – Mood Stabilizers SNRI NDRI MAOI & TCA ECT TMS 0 1 2 3 4 5 6 7 VNS 8 Failed Treatment Attempts in Current Episode Treatment-Resistance Continuum Kessler RC et al. Arch Gen Psychiatry. 2005; 62(6): 617 -627; Kessler RC et al. JAMA. 16 2003; 289(23): 3095 -3105; Herrmann RC. Am J Psychiatry. 1995; 152(6): 869 -875. 16

Electroconvulsive Therapy ECT is the electrical induction of a generalized seizure under general anesthesia for therapeutic purposes In the USA, ECT is one of the most common procedures (>100, 000/year) performed under anesthesia and the safest with a mortality rate ≤ 0. 002% Two treatment schedules are used: – An acute course (2 - 3 times per week for 3 -6 weeks) achieves current episode remission – Continuation/Maintenance ECT every 2 – 6 weeks to inhibit recurrence 18

What is TMS? (Transcranial Magnetic Stimulation) 1831 – Michael Faraday, principles of magnetic induction 1985 – Anthony Barker, first electromagnet for human use (spinal cord. . ) 1995 – NIH, first TMS trial for TRD Electric current through the coil induces MRI-strength magnetic field Magnetic field pulses pass 2 -3 cm into the cortex inducing electrical current in the brain This stimulates the firing of nerve cells and the release of neurotransmitters 30 treatments, with no anesthesia, 5 days/week, for 26 -40 minutes each 1 Richelson, E. Mechanisms of Action of Repetitive Transcranial Magnetic Stimulation (r. TMS) and Vagus Nerve Stimulation (VNS). Psychiatric Annals, 2007; Vol 37 -No. 3, 181 -187. 19

SEASONAL AFFECTIVE DISORDER (SAD)

DSM-V Criteria For MD Seasonal Pattern Specifier • Regular temporal relationship between the onset of a major depressive episode and a particular time of the year (not including seasonal stressors – layoffs, holidays. . . ) • Full remissions at a particular time of year • 2 depressive episodes in the last 2 years to demonstrate the temporal / seasonal relationship, no non-seasonal episodes • Seasonal episodes > non-seasonal • Symptoms cause significant distress or impairment in social, occupational or other areas of functioning

SAD Symptoms Similar to “Atypical” Depression Energy Crisis Hypersomnia, fatigue Irritability Decreased concentration Loss of interest in routine activities • Increased appetite • Carbohydrate craving • Weight gain • • •

Prevalence Of SAD In North America § 6% overall in the U. S. § 10% in northern regions (U. S. , Canada, Scandanavia…) § 1 - 2% in southern areas § 2 - 9 times more common in females § 50% have 1 st degree relative with mood disorder § >20% in those with major depression § 10% of all SAD symptomatic in summer § Seasonal patterns identified in bulimia, anxiety disorders and other mood disorders

Total Daylight Hours On Shortest Day Of The Year In Northern Latitudes • • Fairbanks, AS Anchorage, AS Vancouver, BC Toronto, ON Detroit, MI S. F. , CA Miami, FL 65 deg 61 deg 50 deg 43 deg 42 deg 38 deg 26 deg 3 h 42 m 5 h 28 m 8 h 11 m 8 h 56 m 9 h 4 m 9 h 33 m 10 h 26 m

Lake Effect • Cold air masses moving south and east across the relatively warmer waters of the Great Lakes produces clouds • Late fall and early winter are when there is the greatest differences in temperature between the air masses and lakes • This difference leads to heavy cloud cover in the Upper Peninsula and western Lower Peninsula

Average Cloudy Days / Year In Michigan Sault Ste. Marie Grand Rapids Muskegon Houghton Lake Flint Alpena Lansing Detroit 209 205 202 200 195 194 191 185

SAD Theories • Physiological vulnerability to experience atypical mood symptoms during winter • Circadian rhythm dysregulation, melatonin • Neurotransmitters - serotonin, norepinephrine, dopamine • Psychological vulnerability to develop mood symptoms in response to vegetative symptoms (decreased activity, increased sleep + appetite)

Circadian Rhythm • Human brain has a 24 hour repeating rhythm to regulate day and night activities • Melatonin secreted by the pineal gland in response to darkness and induces sleep • Melatonin levels peak ~ midnight to 2 am then fall gradually until morning • Morning light sensed by the retina informs the brain of a new day, suppressing melatonin • Winter with less morning light, melatonin levels peak later and remain elevated 2 or more hours longer – body thinks it needs more sleep

Circadian Rhythm: Peak Time of Functions Gastric acid secretion WBC Growth hormone Peripheral blood flow Prolactin Urination Cholesterol/ Triglycerides midnight 6 pm Insulin Melatonin 6 am noon Respiratory Rate Cortisol Blood Pressure/ heart rate Arterial elasticity/ venous resistance Platelet adhesiveness Hemoglobin Blood viscosity

CHANGES IN LATITUDE + HOURS OF DAYLIGHT + LAKE EFFECT CLOUDS + CIRCADIAN RHYTHM CHANGES IN ATTITUDE Apologies to Jimmy Buffett

“It is certainly very cold, ” said Peggotty. “Everybody must feel it so. ” “I feel it more than other people, ” said Mrs. Gummidge. Charles Dickens, David Copperfield

“Growing up in a place that has winter, you learn to avoid self-pity. Winter is not a personal experience; everyone is as cold as you are; so don’t complain about it too much. It could be worse”.

SAD Theories - Melatonin • Sleep promoting hormone 90% from pineal gland, 10% from retina • Dim and bright light suppresses secretion • Body temperature drops as melatonin levels rise at night, with darkness • SAD individuals show longer duration of melatonin release through the nights/winter • Beta-blockers (propranolol, atenolol…) suppress secretion but are effective only for 1 -2 weeks

SAD Studies • SAD / depressed patients use more medical resources, prescriptions, tests, referrals… • Retinal sensitivity decreased with age • Increased serotonin turnover on sunny days • Visual impairment not a factor, myopia? • Decreased attention and concentration (NE, DA? ) • Bright light therapy offers some improvement in non-SAD mood disorders • High carbohydrate diet increases energy in those w/ SAD, non-SAD persons felt lethargic

Prevalence of SAD, WB by Latitude Location Latitude SAD WB Total Sarasota, FL 27 1. 4 2. 6 4. 0 Maryland 39 6. 3 10. 4 16. 7 New York City 40 4. 7 12. 5 17. 2 Nashua, NH 42 9. 7 11. 0 20. 7 Fairbanks, AK 65 9. 2 19. 1 28. 3 Stockholm, SE 59 3. 9 17. 8 Helsinki, FI 59 7. 1 11. 8 18. 9 Oslo, NO 59 14. 0 12. 6 24. 6 Reykjavik, IS 64 3. 8 7. 6 11. 3 Tromso, NO 69 13. 7 10. 7 24. 4 Nagoya, JP 35 0. 9 0. 8 1. 7

Genetic predisposition? No difference in Finns vs. Lapps of Norway 3 x prevalence in Asians living in Britain Less prevalence in Iceland vs. Eastern US 2 x prevalence in Russians vs. Norwegians Acclimatization? – fewer seasonal symptoms in those living in an area for a longer time • Japanese in Stockholm had more seasonal variation over time • • •

SAD Treatments • Bright light therapy • Sleep deprivation • Antidepressants - Prozac = BLT, Wellbutrin XL (FDA approved for episode prevention) • Tricyclic, MAOI antidepressants • Stimulants - Ritalin, Adderall, Dexedrine, Provigil, Nuvigil… • 30 -60 minutes of morning exercise • Psychotherapy – CBT, Mindfulness, TM. . .

Supplements Chromium Picolinate • Studied for mood effect in SAD, 600 mcg daily • No mood effect found • Decreased carbohydrate cravings, food intake • Minimal side effects – insomnia, headache, irritability, nausea Melatonin • 1 -10 mg, 1 -2 hours before bedtime • Minimal tolerance or daytime sedation • Rare drug interactions

Bright Light Therapy - Studies • > 200 studies since 1979, poor funding, small studies • Recognized effective treatment since 1984 • Morning vs. midday vs. evening • Difficult to include placebo • Eyes vs. skin • Duration • Distance • Color, frequency

Meta-analysis of Studies Diagnosis/treatment Effect size Clinical effect Bright light 0. 84 Large Dawn simulation 0. 73 Large Bright light 0. 53 Medium Adjunctive bright light 0. 01 None Seasonal Affective Disorder Non-seasonal depression

Measurement Of Illumination - LUX • 100 w bulb at 3 ft 100 • Fluorescent overhead at 3 ft 400 • Ambient light home 500 • Sky at twilight 750 • Phototherapy Light Box • Bright, overcast day • Clear, noon - temperate • Clear, noon - equator 2, 500 -10, 000 10 - 25, 000 80, 000 100, 000

Blue Light Special? • Visible light spectrum 400 -700 nm, Sunburn from UV rays, <400 nm Incandescent lamps have most output near infrared end of spectrum • Retinal sensors - Rods (B&W) and Cones (color) may not be involved in light transmission for circadian/melatonin effect • Ganglion cells of retina coated with melanopsin responds preferentially to 446 – 477 nm (blue) which

Blue Light Special? • Light triggers retinal sensors, especially melanopsin, sending signals to the suprachiasmic nuclei of the hypothalamus to turn off melatonin production • Blue wavelengths are close to UV in spectrum, poorly calibrated light could be dangerous • Increased risk of macular degeneration? • Cataracts may filter out blue light • Some clinicians recommend use of goggles to filter out Blue / UV rays when using BLT

Blue Light Special? White Light Blue Light Wavelengths 400 - 700 nm 440 - 480 nm Brightness for clinical effect 3000 - 10, 000 lux 400 - 3000 lux Efficacy Well-established Safety Well-established Few trials, conflicting results Controversial Advantages Long-track record Lower intensity for effect

Phototherapy Lights • • Insurance may cover as medical equipment Full spectrum fluorescent vs Blue LED Dawn simulation Visor

Bright Light Therapy • Morning light - advance melatonin rhythm • Evening light - delay melatonin rhythm, may be beneficial for elderly to delay early bedtime • Both can improve SAD symptomsmost studies show superiority of am light • Improved atypical sx better more than exercise • Severity of overeating/oversleeping are best predictors of improvement with light therapy • Possible benefit in PMDD, Bulimia, Adult ADHD • Safe in pregnancy

Bright Light Therapy • 70% response rate in SAD, similar to medications for MD • 2 – 4 days for onset of effect • 2 – 4 weeks for peak treatment effect • 2, 500 - 10, 000 lux for 30 minutes – up to 2 hours/day (typical box has 10, 000 lux @ 20 inches, 2, 500 @ 40 inches) • Early morning most beneficial - Start with am light for 2 -3 weeks, change to pm light if am is ineffective • Cool white fluorescent = full spectrum • Dawn simulation (<100 lux) – 1 - 2 hrs am brightening • Dim light visor for 30 - 60 minutes

Light Therapy Potential Side Effects • • • Eyestrain Headache Anxiety Restlessness Irritability Nausea Dizziness Insomnia Muscle tension • Relatively contraindicated in those with retinal and optic nerve disorders, glaucoma, cataracts, SLE, skin CA • Photosensitizing drugs – diuretics HCTZ, herbals SJW, antibiotics tetracycline, antipsychotics thorazine • No evidence of long term adverse effects

SAD Studies - Cognitive Behavioral Therapy • SAD and nonseasonal depressed patients exhibit similar ANTs toward themselves and environment. • SAD females > males show this negativity all year • Negative cognitions relating to winter, light availability, weather/environmental cues identified and challenged. • Schedule winter activities to counteract ‘hibernation’. • CBT found to be as effective as light therapy for episode. May be more effective for future relapse prevention. • Aerobic exercise- (morning / afternoon, 60 min. / daily) shown to be effective in depression and SAD, especially under bright lights. (Normalization of daily calorie expenditure as an underlying cause? )

SAD Survival Guide Get out of the house - bundle up, walk… Get off of the couch – exercise, hobbies, sports Bright lights, shades up, curtains open. . . Sleep hygiene – regular sleep/wake times Avoid napping – keep them brief and regular Don’t expect a vacation miracle cure Watch what you eat – maintain a balanced diet (fresh fruits, salads…) • Beach / tropical music and boat drinks? • •

Resources • Lam, R. “Seasonal Affective Disorder and Beyond” • Rosenthal, N. E. “Seasonal Affective Disorders & Phototherapy” “Seasons Of The Mind” “Transcendence: Healing and Transformation through TM” “Winter Blues” 4 th ed. 2013 • Terman, M. - “Chronotherapy: Resetting Your Inner Clock to Boost Mood, Alertness and Quality of Sleep”

Resources - Websites (www. ) • Lighttherapy. com (Philips) • Sunbox. com • Fullspectrumsolutions. com • Feelbrightlight. com • SADlamps. org • Bio-light. com • Northernlighttechnologies. com • Litebook. com • Normanrosenthal. com • Biobrite. com • Lighttherapyproducts. com

Resources • National Institute of Mental Health www. nimh. hih. gov • National Alliance for the Mentally Ill www. nami. org • Depression & Bipolar Support Alliance www. dbsalliance. org • Center for Environmental Therapeutics www. cet. org • Beck Institute for CBT www. beckinstitute. org • Society for Light Therapy and Biological Rhythms www. sltbr. org

Seasonal Affective Disorder Growing up in a place that has winter, you learn to avoid self-pity. Winter is not a personal experience, everyone else is as cold as you, so you shouldn’t complain about it too much. You learn this as a kid, coming home crying from the cold, and Mother looks down and says, “It’s only a little frostbite. You’re okay. ” And thus you learn to be okay. What’s done is done. Get over it. Drink your coffee. It’s not the best you’ll ever get but it’s good enough.