1. Human Behavioral Development & Problems: Adolescent Depression & Suicide Gary L. Davis, Ph.D. Dept. of Behavioral Sciences

2. Minnesota Prevalence of Mental Health Disorder 11% (274,000) of people enrolled in MN health plans have been Dx’d with a mental health disorder (Feb, 2008). 10% of children and adolescents had a mental health related dx Most common dx: AD/HD, depression, anxiety >80% of psych meds are prescribed by primary care 97% of children did not receive FDA recommended follow-up care.

3. Most Frequently Prescribed Psychotropics (2006) Escitalopram (Lexapro)-5th ssri Zolpidem (Ambien)-9th nonbenzo hyp Sertraline (Zoloft)-10thssri Venlafaxine (Effexor-XR)-13thsnri Bupropion (Wellbutrin XL)-24th ndri Quetiapine (Seroquel)-37thantipsych Amphetamine salts (Adderall XR)-42nd stim Duloxetine (Cymbalta)-43rdsnri

4. Mechanisms of Action of Antidepressants 1. Monoamine neurotransmitter reuptake blockade Tricyclic anti-depressants (TCA’s) e.g. amitriptyline Selective serotonin reuptake inhibitors (SSRI’s) Serotonin/Norepinephrine reuptake inhibitor (Venlafaxine) Norepinephrine/Dopamine reuptake inhibitor (Bupropion) Serotonin-2 antagonist/reuptake inhibitor (Nefazodone, trazodone) 2.Monoamine oxidase inhibitors (MAOI’s) e.g Parnate 3.Norepinephrine alpha 2 antagonist--blocking alpha 2 receptors “cuts the brake cable” on the release of NE ( Mirtazepine )

5. Tricyclic Anti-Depressants (TCA’s)

6. Tricyclic Antidepressants (TCAs) Adverse Reactions Anti-cholinergic –Dry mouth –Blurred vision –Constipation –Urinary retention Alpha adrenergic blockade –Dizziness –Orthostatic hypotension Antihistaminic –Sedation –Weight gain Cardiac effects –Tachycardia –Prolonged conduction time (  QT interval) –Arrythmia at high dose/overdose

8. Selective Serotonin Reuptake Inhibitor (SSRIs)

9. Currently Available SSRI’s Fluoxetine* (Prozac, Sarafem, Prozac Weekly) Sertraline* ( Zoloft) Paroxetine* (Paxil, Paxil CR) Fluvoxamine* (Luvox) Citalopram* (Celexa) Escitalopram (Lexapro) * Available as generic

11. Selective Serotonin Reuptake Inhibitors (SSRIs) Action: Inhibits the transporter for Serotonin (and NE). SSRIs have multiple binding sites which may contribute to their overall clinical effects, tolerability from one agent to another and one patient to another. Indications: 1 st line treatment of depression Mild/moderate depression and dysthymia Obsessive compulsive disorder Panic and social phobia Bulimia PTSD Generalized anxiety disorder

12. SSRI Action

13. Serotonin Syndrome Autonomic: diaphoresis, hyperthermia, hypertension, tachycardia, shivering, diarrhea Neuromotor: hyperreflexia, myoclonus, restlessness, tremor, rigidity, seizures Psych: confusion, anxiety, insomnia, hallucinations, agitation

15. Serotonin/Norepinephrine Reuptake Inhibitors-Venlafaxine(Effexor); Duloxetine(Cymbalta)

17. Affinity for 5HT v. NE transporters Duloxetine (Cymbalta)20 Venlafaxine (Effexor)120* Fluoxetine (Prozac)290 Paroxetine (Paxil)320 Sertraline (Zoloft)1400 Citalopram (Celexa)3600

18. Norepinephrine/Dopamine Reuptake Inhibitor- Bupropion (Wellbutrin, Zyban)

19. Serotonin-2 Antagonist/Reuptake Inhibitor (Nefazodone--Serzone, Trazodone--Desyrel)

20. Monoamine Oxidase Inhibitors (MAOIs)

21. Pharmacotherapy of Depressions 1st line agent –SSRIs (fluoxetine--Prozac, sertraline--Zoloft, paroxetine--Paxil, citalopram--Celexa, and escitalopram--Lexapro) –Venlafaxine (SNRI)--Effexor 2nd line agents –Bupropion (NDRI)--Wellbutrin –Duloxetine (SNRI)--Cymbalta 3rd line agents –TCAs –Mirtazepine (alpha 2 antagonist)--Remeron 4th line agents –MAOIs –Nefazodone (SARI)--Serzone??

22. Antidepressants Side effects are receptor level actions— Therapeutic effects MAY be due to receptor down-regulation (5HT2) and desensitization secondary to intra-cellular effects “50-65%” response to 1st agent (10-15% to 2nd agent)-clinical trials Interactions with other drugs due to induction/inhibition of CYP450 enzymes

23. Antidepressants (cont’d) Some are notorious for side effects Sometimes augmented with other drugs, e.g., other anti-depressants, Lithium, thyroid hormone, methylphenidate Most are known to cause withdrawal symptoms if abruptly discontinued (discontinuation syndrome) Non-depressed experience side effects, not mood enhancement, although some research suggests modification of certain personality characteristics (e.g., shyness, aggressiveness)

24. Time Course of Response to Anti-depressants Weeks 1-2: sleep, appetite, anxiety Weeks 3-4: energy, anhedonia, sex Weeks 4-6+: mood

25. The FDA Controversy: Teenagers and Antidepressants Recent meta analysis of 24 studies 4400 patients Antidepressants vs. placebo Duration was on 1 to 4 months

26. FDA Findings No one committed suicide in these studies 4% became suicidal on meds, 2% on placebo Suicidality developed early in treatment Risk was lowest with Prozac, highest with Effexor

27. FDA Recommendations Black box warning Antidepressants increase suicidality in children and adolescents Balance risk of suicidality with clinical need Patients should be observed closely (weekly follow- up for 4 weeks, then biweekly for a month, then quarterly) Families and caregivers should observe A statement about whether the drug is approved for pediatric indication

28. Antidepressants with Pediatric Indications Prozac: MDD, OCD Zoloft, Luvox, Anafranil: OCD

30. Adolescent 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.

31. Adolescent Depression Dysthymic Disorder –Depressed mood for at least one year, plus 2 or more of the following: –Under or over-eating –Insomnia or hypersomnia –Low energy –Low self-esteem –Poor concentration or indecision –Hopelessness

32. Adolescent Depression –Bipolar disorder = depression plus: Symptoms of mania Severe changes in mood — either extremely irritable or overly silly and elated Overly-inflated self-esteem; grandiosity Increased energy Decreased need for sleep — able to go with very little or no sleep for days without tiring Increased talking — talks too much, too fast; changes topics too quickly; cannot be interrupted

33. Adolescent Depression Bipolar disorder (cont ’ d) Distractibility — attention moves constantly from one thing to the next Hypersexuality — increased sexual thoughts, feelings, or behaviors; use of explicit sexual language Increased goal-directed activity or physical agitation Disregard of risk — excessive involvement in risky behaviors or activities

34. Adolescent Depression Signs that may be associated with depression in children and adolescents –Frequent vague, non-specific physical complaints such as headaches, muscle aches, stomachaches or tiredness –Frequent absences from school or poor performance in school –Talk of or efforts to run away from home –Outbursts of shouting, complaining, unexplained irritability, or crying –Being bored –Lack of interest in playing with friends –Alcohol or substance abuse –Social isolation, poor communication –Fear of death –Extreme sensitivity to rejection or failure –Increased irritability, anger, or hostility –Reckless behavior –Difficulty with relationships

35. Adolescent Depression Co-morbidity –ADHD –Conduct disorder –Delinquency –Drug/alcohol –Anxiety –Eating disorder

36. Psychosocial Factors in Depression Risk factors –Limited social support –Hx of early parental loss –Female gender –Family hx of depression –Introverted personality style –Negative life events/adverse childhood experiences –Cigarette smoking –Attentional/conduct/learning problems

37. Psychosocial Factors in Depression Reduced reinforcement –Few available potentially reinforcing events related to personal characteristics –Little available reinforcement in the environment –Few effective behaviors and skills available Cognitive factors/dysfunctional thinking –Negative view of self, world, and future –Cognitive "set" distorts and filters perceptions 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

38. Assessment Screening tools — Beck Depression Inventory, Center for Epidemiological Studies — Depression, Children ’ s Depression Inventory Clinical Interview

39. Worries and Concerns of Adolescents- Results from the MN Adolecent Health Survey

43. Adolescent Suicide Facts ( www.nimh.nih.gov/health/publications/ suicide-in-the-us-statistics-and- prevention.shtml ) www.nimh.nih.gov/health/publications/ Psychological disorders linked to suicide –Mood disorder –Alcohol and drug abuse –Conduct disorder, anti-social traits –Panic disorder –Schizophrenia –PTSD

44. Adolescent Suicide Risk factors –Sex –Availability of firearms –Psychological disorder –Poor problem-solving skills –Family hx of suicide/mood disorder –Substance abuse –Sexual/physical abuse –Prior suicide –Aggressiveness –Concerns re: sexual orientation –Mass media coverage –Adverse childhood experiences (ACEs)

45. Adolescent Suicide JAMA Study — Childhood abuse, household dysfunction and the risk of attempted suicide throughout the life span

48. Adolescent Suicide Assessment –Risk factors –Crisis-intent, plan, means –Evaluating seriousness of an attempt –Triggers or stressors Intervention –Safety –Support –Admit? –Refer for therapy –Medication