Pharmacology of Antidepressants and Anti-anxiety Agents

1. Pharmacology of Antidepressants and Anti-anxiety Agents AneetAhluwalia, MD Assistant Professor of Psychiatry and Internal Medicine

2. Case • 47-year-old woman presents to PCP with CC: fatigue. She indicates that she was promoted to senior manager in her company approximately 11 months earlier. Although her promotion was welcome and came with a sizable raise in pay, it resulted in her having to move away from an office and group of colleagues she very much enjoyed. In addition, her level of responsibility increased dramatically.

3. The patient reports that for the last 7 weeks, she has been waking up at 3 AM every night and been unable to go back to sleep. She dreads the day and the stresses of the workplace. As a consequence, she is not eating as well as she might and has dropped 7% of her body weight in the last 3 months. She also reports being so stressed that she breaks down crying in the office occasionally and has been calling in sick frequently. When she comes home, she finds she is less motivated to attend to chores around the house and has no motivation, interest, or energy to pursue recreational activities that she once enjoyed such as hiking. She describes herself as "chronically miserable and worried all the time."

4. Her medical history is notable for chronic neck pain from a motor vehicle accident for which she is being treated with tramadol and meperidine. In addition, she is on propranolol for hypertension. The patient has a history of one depressive episode after a divorce that was treated successfully with fluoxetine • CBC, TSH, CHEM 7 WNL.

5. Criteria for Major Depression -SIGECAPS, anhedonia or depressed mood, impairment in functioning

6. Major Depression Epidemiology • Point Prevalence males 2-3 %, females 4-9% • Lifetime Risk males 7-12 %, females 20-25% • Major Depression is 4th leading cause of disability worldwide (this is probably an underestimate)

7. Risk Factors for depression • Family history of mood disorder • Previous Episode • Stress • Emotional trauma • Childhood abuse/neglect • Elderly (over 65) • Marital factors (single, separated, divorced, or unhappily married)

8. Risk Factors for depression-Cont • Substance abuse • Physical illness • Heart disease • Diabetes • Obesity • Cancer • Menopause • Rhematoid arthritis

9. Prevalence of Depression in Medical Illnesses Musselman et al., Arch Gen Psych 1998, Biol Psych 2003; Cohen-Cole & Kaufman, Depression 1993

10. Depression-consequences • Suicide • Suffering • Impaired relationships • Impaired job/school performance • negatively influence other medical conditions and is a risk factor for medical M&M • Co-morbid anxiety is common, and can increase suicide risk

11. Genetics or Environment? • Genetics and Environment both contribute • Commonly accepted theory is that multiple gene loci are implicated, and these loci make people more vulnerable to environmental stressors, leading to increased risk for MDD • Why not one gene? Because depression is a heterogeneous disorder that is not just one entity (different subtypes of depression), with different biological, psychological, and social causes

12. Presentation • Adults can present with various somatic complaints (such as lower back pain, headache, CV, GI, GU) or decreased energy rather then complaints of depression • Elderly can present with cognitive deficits (pseudodementia-poor effort) as well as somatic complaints

13. Treatment • Depression can be treated with psychotherapy, with medication, or with the combination of therapy and medication • For moderate to severe, medication plus therapy is the best option • Placebo response ~0.4 compared to antidepressant response ~0.7

14. Possible Biological Markers • Decreased BDNF in serum • Low tryptophan, 5HT, and 5HIAA (metabolite of 5HT) in postmortem suicide patients • Polymorphisms of 5HT1a receptors with decreased affinity for 5HT have been shown to increase risk for depression when stressed • We can induce depression by tryptophan restriction (tryptophan is a precursor to 5HT) • Norepinephrine and Dopamine are thought to be low in depression

15. Symptoms clusters and Neurotransmitters General Anxiety, obsessional depressive thoughts Serotonin dysfunction Anhedonia, psychomotor retardation Dopamine dysfunction Panic Gabadysfunction fatigue, poor concentration Norepinephrine dysfunction

17. Antidepressants/Antianxiety • SSRIs-prevent reuptake of serotonin (5HT) • SNRIs-prevent reuptake of serotonin and NE • DNRI-prevent reuptake of NE and D • MAOI-prevent breakdown of monoamines • 5HT1A partial agonist • BZD/anticonvulsant-increase action of Gaba • Antihistamine • Block alpha 1, alpha2 agonist • Beta blockers

18. Brain Imaging findings in depression • Decreased frontal blood flow (~7 %) • Lower hippocampal volume

19. HPA-hypothalamic pituitary adrenal axis Stress causes a release of CRH, ACTH, and ultimately cortisol. This is beneficial, as we need the increased glucose it causes and increased blood pressure to deal with the stressor at hand.

20. HPA- stress • When exposed to chronic or extreme stress, cortisol, ACTH, and CRH levels are at higher levels, and stay elevated for longer periods of time

21. So what? We’re not endocrinologists • Cortisol and CRH have been shown to cause damage to hippocampal neurons by causing decreased dendritic branching and decrease in pyramidal neuron spines

22. What does BDNF do? • Promotes synaptic plasticity, neuronal growth, neuronal spine formation, especially in hippocampus • Also helps cell survival and resilience • Reduces apoptosis • Shown to be low in patient with depression • Increased BDNF expression in hippocampus of depressed patients treated with antidepressants compared to untreated

24. How do stress and hormones cause these neuronal changes • Stress and glucocorticoidssupress expression of Brain derived Neurotropic growth factor. • Decrease in volume of hippocampus is proportional to length of depression • Prozac has been shown to increase hippocampus synaptogenesis in rats after 5 days treatment (?mechanism of action?)

25. Examination of Cues-evolution • LOSSES that cause sadness are of reproductive resources • Money, a mate, reputation, health, relatives, friends…. • These things, in theory, would have increased reproductive success (evolutionarily speaking)

26. LOSS = Signal of Maladaptive Functioning • If Loss triggers sadness • And • If sadness changes our behavior to stop current losses, and prevent future ones…. • Then • That would be useful, indeed!

27. Medical causes of depresion • Hypothryoidism • Stroke • Multiple sclerosis • hyper/hypo parathyroidism • Addisons disease • Cushings disease • Hypopituitarism • Anemia

28. Anxiety Response Cues Panic = fear imminent death Social = fear embarrassment PTSD = emotional memory of trauma OCD = intrusive obsessions GAD = free-floating; no conditioned specific triggers

29. Generalized Anxiety Disorder • prevalence of GAD of 5.1 percent to 11.9 percent. More common in women than men (2 to 1) • One of the most common illnesses you will encounter in primary care as it is common in the medically ill. • Associated with increased health care utilization

30. Generalized Anxiety Disorder aka GAD • Excessive worrying that is difficult to control occurring more days than not for 6 months causing significant distress/impairment "Do you worry excessively about minor matters?“

31. GAD 3 of the following symptoms Restlessness easy fatigued or poor sleep difficulty concentrating Irritable muscle tension

32. GAD • Usually fairly chronic • Hereditary component—shared neuroticism, depression and GAD • Learned behaviors • Environmental triggers • GAD in adult life is associated with a higher-than-average number of traumatic experiences and other undesirable life events in childhood

33. GAD -treatment • Therapy and meds both effective as is the combination • SSRIS first line, other agents helpful as well such as SNRIs and BZDs • Adjunctive treatment –accupuncture, yoga can be helpful

34. Panic disorder --classic, discrete episodes of intense fear that begin abruptly and last for several minutes to an hour. --often have chest pain, feeling of rapid heartbeat, or shortness of breath – frequently precipitating an emergency room visit.  --recurrent, unexpected panic attacks, and one month or more of either worry about futureattacks or consequences, or a significant maladaptive change in behavior related to the attacks, such as avoidance of the precipitating circumstances,agoraphobia can occur.

35. Treatment for Panic • Meds and Therapy are both equally effective, combo is slightly better • SSRIS first line, BZDs as well and SNRIs

36. OCD

37. OCD Obsessions contamination pathological doubt aggressive impulses somatic concerns need for symmetry sexual impulses

38. OCD Compulsions cleaning washing checking excessive ordering/arranging counting repeating collecting

39. OCD 2-3% Americans (or 1 in 50) Men=women Onset generally in adolescence or early adulthood Chronic waxing and waning course Fist line treatments are SSRIs and CBT

40. Selection of Medication • Family History of response • Past treatment response • Specific symptoms (with anxiety SSRI, Low energy SNRI or WB) • Medication interactions • Medical conditions • Side effect profile • *important to educate about SE, what to expect, and length of time for response to increase compliance (don’t sensitize them)

41. SSRIs prevent reuptake of serotonin Take 2-6 weeks for full effect, usual length of treatment at least 3-6 months 5HT1 - fights depression 5HT2 - tremors, sweating, decreased libido, activation 5HT3 – nausea, diarrhea (ondansetron blocks this receptor)

42. SSRIS • Some DDIs- tramadol, mepiridine, dextromethorpan, linezolid, tamoxifen, clopidogrel

43. Fluoxetine=Prozac -10-80 mg titrate to effect -Long half life -activating and ass with weight loss -start at 10 & increase to 20 after ~1 week -Inhibits 2D6 raising levels of beta blockers, also lowers level of active metabolite of clopidigrel, avoid with tamofixen

44. Citalopram and Escitalopram • Citalopram is a mixture of 2 enantiomers while escitalopramis just the more active enantiomer • 5 mg escitalopram=10 mg citalopram • Maximum mean prolongations in the QTc intervals were 8.5 and 18.5 ms for 20 and 60 mg citalopram, respectively

45. Sertaline=zoloft • Start 25 and increase to 50. 200 mg max • Effective, generic • Most studied SSRI in pregnancy and breast feeding and 1st line • Inhibits 2D6--Increased beta blocker, decreased active metabolite of tamofixen, decreased levels of active metabolite of clopidogrel • More nausea/diarrhea than other SSRIS?

46. Paroxetine=Paxil • Most sedating, most weight gain, worst discontinuation syndrome • Start at 10 mg and titrate up • Has anticholinergic and antihistaminergic activity • DDIs - can increase beta blockers and lower levels of active metabolite of tamoxifen

47. Fluvoxamine-luvox • Marketed for OCD • Not used as often • 50-300 mg

48. SSRI possible side effects • Appetite loss or Increase • Weight gain, weight loss • Nausea, Diarrhea • Decreased libido, delayed ejaculation or anorgasmia (10-30 %) • Akasthisia–inner restlessness (rare, usually at start) • Fatigue, sleepiness or sleeplessness (can use Benzos or newer sleep medications as needed short term) • Long term use can cause apathy at high doses • Can cause hypomania or mania in bipolar patients • Dry mouth • Hyponatremia/SIADH (rare) • Vivid dreams • Increase in suicidal ideation in adolescents • QT prolongation

49. Rare serious side effects • Serotonin syndrome- rare, presents with high fevers, sweating, diarrhea, myoclonus, hyperreflexia, muscle rigidity, tachycardia, hypertension, elevated CK, nausea. • Risk factors: combining SSRI and MAOI, using higher doses and multiple serotonergic medications (meperidine, tramadol)—also can cause seizure • Dextromethorphan not contraindicated, but does increase serotonin levels • Treatment involves IV fluids and Benzos, dantrolene can also be used.

50. Perfect patient for SSRI • Depression and anxiety patient in initial case-though consider tramadol decrease or cessation