Psychiatry Update

Christopher Schneck, M.D. Associate Professor of Psychiatry Medical Director, CU Depression Center Mental Health Director, UCH ID/HIV Clinic

February 7th , 2015

Disclosure: Funding Sources Research Funding: Consulting Fees: •National Institute for Mental Health •None •Crown Family Foundation Stock Holdings (>$10,000) Salary Support: •None •Ryan White HIV/AIDS Funding

Speakers Bureau: •None

Consulting: •None

Course Objectives

• Understand evaluation of insomnia and current treatment options ; • Understand the latest treatments for major depression; • Understand the latest treatments for bipolar disorder; • Understand assessment and treatment of ADHD in adults. Insomnia Assessment

• Sleep onset vs maintenance • Nighttime routine – Setting: dark room, clock, temp – Habit: time in bed, time to sleep, awakenings during the night, early morning awakening • Patients: over-estimate sleep latency, wakefulness after sleep onset, underestimate sleep duration • Sleep diaries

Buysse DJ et al. JAMA. vol 309(7), 2013.

Pluses and Minuses of Prescribing Sleeping Medications + _ • They often work! • Issues of physical and psychological • Initial relief of insomnia, improved therapeutic dependence alliance, • Insidious effects of long- term alteration of sleep • Mood stabilizing architecture

• Tolerance, rebound • Abuse, falls, memory, MVAs • Sleep eating/walking

FDA-Approved Medications for Insomnia

Antihistamine Benzodiazepine Barbituate •Diphenhydramine Receptor Agonists •Pentobarbital •Doxylamine •Zolpidem (Ambien) •Secobarbital •Zaleplon (Sonata) •Butalbital •Eszopiclone (Lunesta) Benzodiazepines •Estazolam (ProSom) Unknown Mechanism •Flurazepam (Dalmane) Melatonin Receptor •Chloral Hydrate •Quazepam (Doral) Agonist Temazepam (Restoril) • •Ramelteon (Rozerem) •Triazolam (Halcion) Orexin Antagonist Tricyclic Antidepressant • Suvorexant (Belsomra) •Doxepin Non-FDA Approved Medications for Insomnia

Anxyiolytic Benzodiazepines Antidepressants • Clonazepam • Trazodone • Alprazolam • Mirtazapine (Remeron) • Diazepam • Amitriptyline

Atypical Antipsychotics Melatonin Receptor Agonists • Quetiapine (Seroquel) • Melatonin • Olanzapine (Zyprexa) Alternative/Herbal •Valerian Root extract

Selecting Treatment

• Difficulty initiating sleep (35-60%) – Short-acting, rapid-onset agent (e.g. zolpidem, zaleplon) • Difficulty maintaining sleep (50-70%) – Longer-acting agent (e.g. eszopiclone) or – Shorter-acting for nocturnal awakening (e.g. zaleplon)

Benzodiazepines

Medication Duration of Half-life Dose Indication Action Triazolam Short 2-5 0.125-0.25 mg Onset (Halcion) Estazolam Intermediate 10-24 0.5-2 mg Maintenance (Prosom) Temazepam Intermediate 8-15 7.5-30 mg Maintenance (Restoril) Lorazepam* Intermediate 8-12 1-2 mg Maintenance (Ativan) Quazepam Long 50-200 7.5-15 mg Maintenance (Doral) (active metabs) Flurazepam Long 35 15-30 mg Maintenance (Dalmane Clonazepam* Long 35 0.5-1 mg ????? (Klonopin) *Not FDA approved for insomnia Benzodiazepine-Receptor Agonists

Medication Duration of Half-life (hr) Dose Indications Action

Zaleplon Ultra-short 1 5-20 mg Onset/ (Sonata) Maintenance*

Zolpidem Short 3 5-10 mg Onset (Ambien)

Zolpidem CR Short (80% initial 6.25-12.5 mg Maintenance (Ambien CR) release, 20% delayed) Eszopiclone Intermediate 5-7 1-3 mg Maintenance (Lunesta)

*For maintenance, given on waking during the night Melatonin Receptor Agonists

Medication Duration of Half-life (hr) Dose Indications Action

Melatonin Ultra-short 30-50 Mins 0.3-5 mg Sleep onset, (>1 mg supra- circadian rhythm physiologic) shifting Remelteon Short 2-5 8 mg Onset (Rozerem) Suvorexant (Belsomra)

• Orexin receptor antagonist – Orexin implicated in stimulation of wake- promoting systems and stabilization of sleep- wake cycle • Schedule IV drug • Tabs: 5 mg, 10 mg, 15 mg, 20 mg • TDD NTE 20 mg. Start at 10 mg. • Most common SE: Drowsiness (!)

Sleep Effects of Specific Drugs

Drug Clinical Issues Stg2 EDS SE SL WASO SWS% REM% TST

Trazodone Tolerance can develop to ↑ ↑ ↓ ↓ ↑? ↓ hypnotic effects by week 2

Quetiapine May induce insomnia & ↑ ↑ ↓ ↓ ↓ ↑ “dramatically” ↑s PLMS

BNZOs Drug T1/2 determines ↑ sleep maintenance. ↑ ↑ ↑ ↓ ↓ ↓ Anterograde amnesia.

Non-BNZO Have been associated w/ ↑ ↓ ↓ ↑ agonists sleep-eating. Little effect on sleep architecture.

Stge2= Stage 2; EDS=excessive daytime sleepiness; SE=sleep efficiency; SL=sleep latency; WASO=wake time after sleep onset; SWS=slow wave sleep; REM:=REM sleep latency; TST=total sleep Time; PLMS=Periodic limb movements during sleep From M Reite, M Weissberg et al. Clinical Manual for Evaluation & Treatment of Sleep Disorders. 2009 Behavioral Interventions for Insomnia

Online interventions appear efficacious • Sleep hygiene education • Stimulus control • Sleep restriction therapy • Relaxation training • Cognitive therapy • Cognitive-behavioral therapy for insomnia • Brief behavioral treatment of insomnia

Buysse DJ et al. JAMA. vol 309(7), 2013. Long-term Treatment?

• No well-controlled, prospective objective data on long-term benefit or consequence • Long-term effects of chronic, untreated insomnia • Some data regarding long-term treatment with zolpidem, zaleplon. • Behavioral interventions may create more durable gains.

Jindal RD et al. Am J Psych.2004 New Treatments in Depression Drug Development in the Past 50 Years

16 14 12 10 Depression 8 Schizophrenia 6 Heart Dz 4 2 0 # # of MechanisticallyDistinct Drugs 1950s Present

Insel TR & Scolnick EM. Mol Psych (2006) 11, 11-17 Antidepressants SSRI SNRI TCA Other MAOI Fluoxetine Venlafaxine Amitriptyline Mirtazapine Phenelzine

Paroxetine Desvenlafaxine Nortriptyline Buproprion Selegeline (transdermal) Sertraline Duloxetine Desipramine Trazodone Tranylcypromine Citalopram Levomilnaciprin Imipramine Vortioxetine Isocarboxazid Escitalopram Doxepin (Nefazodone)

Fluvoxamine Trimipramine

Vilazodone* Protriptyline

Amoxapine

Antidepressant Efficacy

• All FDA-approved antidepressants have comparable response rates in placebo- controlled, double-blind clinical trials • There are currently no adequately powered randomized, controlled clinical trials comparing newer medications

Depression Guideline Pane. AHCPR Publication 93-0550. 1993 Slide courtesy M. Thase Thase ME J Clin Psychiatry. 1999;60 (suppl 4) 23 Combining Antidepressants

• Rationale: Two or more different mechanisms of action may yield a superior antidepressant • Not a new strategy: First begun in the 1970s (MAOI + TCA) • Generally safe (except when using MAOIs)

Common Combinations + bupropion SSRI + mirtazapine + bupropion SNRI + mirtazapine SNRI + mirtazapine + bupropion Little Reason: SSRI + SSRI SNRI + SNRI Remission & Response Rates in CO-MED

ESC + PCB BUP SR + ESC VFX XR + MIR Remission Remission Remission Response Response Response 60

50

40

30

20

10

0 12 Weeks 7 Months Acute Phase Continuation Phase Rush AJ et al.am J Psych 2011;168:689-701 Remission & Response Rates in CO-MED

ESC + PCB BUP SR + ESC VFX XR + MIR Remission Remission Remission Response Response Response 60

50

40

30

20

10

0 12 Weeks 7 Months Acute Phase Continuation Phase Rush AJ et al.am J Psych 2011;168:689-701 Recommendations for Prescription of Exercise for MDD

Exercise Domain Recommendation

Modality Aerobic > resistance training

Session frequency 3-5 exercise sessions/week

Session duration 45-60 minutes

Exercise intensity 50-85% max HR (aerobic) or 80% 1-RM (resistance) Intervention duration At least 10 weeks

Rethorse CD & Trivedi MH. J Psych Practice, vol. 19, No. 3 Ketamine: Not Ready for Prime Time

• Schedule III anesthetic agent; street hallucinogen • Extremely rapid antidepressant response on some patients • New mechanism (?) • Studies: 2-week trials, very few patients • Stimulants, opiates comparison • Long-term effects?

Schatzberg AF. Am J Psych.2013 New Treatments in Bipolar Disorder Bipolar Disorder:

Stabilize One Illness, or Many? from Above

Prevention

Stabilize from Below FDA-Approved Therapies for Bipolar Disorder

Bipolar Bipolar Therapy Maintenance Mania Depression Valproic acid √ Yes No No Lithium √ Yes No* √ Yes Carbamazepine √ Yes No No Divalproex √ Yes No No Lamotrigine No No √ Yes Aripiprazole √ Yes No √ Yes Olanzapine √ Yes No √ Yes Olanzapine+fluoxetine (OFC) No √ Yes No Quetiapine √ Yes √ Yes No Risperidone √ Yes No No Ziprasidone √ Yes No No Asenapine √ Yes No No √ Lurasidone No Yes No Treatment of Mania Drugs by overall probability to be the best treatment in terms of both efficacy & dropout rate in Mania

100 Acceptability Efficacy 90 87 79 80 75 70 68 62 60 59 50 50 43 41 40 39 30 23 21 20 7 10 3 0

Cipriani A et al. Lancet Oct, 2011. Treatment of Bipolar Depression Lurasidone Monotherapy Trials: Responder & Remitter Analysis

Responders Remitters

60% *** 53% *** 51% 50% ** ** p<.01 ** 42% *** p<.001 40% 40% Effect Size 30% LUR 20-60 mg: 0.51 30% LUR 80-120 mg: 0.51 25%

20% Proportion of Patients 10%

0% PCB LUR LUR PCB LUR LUR N=162 20-60 mg 80-120 mg N=162 20-60 mg 80-120 mg N=161 N=162 N=161 N=162 Loebel A et al. ICBD, 2013 Observed Magnitude of Antidepressant Effect QUE=quetiapine LTG=lamotrigine OFC=olanzapine/ fluoxetine LUR=lurasidone OLZ=olanzapine

1.2 1.1

1 Effect size (ES) = improvement over placebo/pooled SD. 0.9 small < 0.4 Bipolar I moderate 0.4–0.79 large > 0.79. 0.8 0.7 0.7 0.65 0.6 Bipolar II

Size Effect 0.51

0.4 0.4 0.3 0.3

0.2

0 QUE QUE LTG OFC LTG LUR OLZ QUE QUE 600 300 200 50 80- 600 300 120

Adapted from Calabrese JR. presented at: APA 2005 Annual Meeting, 2005 Atlanta, GA. Positive Antidepressant Trials with Adequate Sample Size* in Bipolar Depression

*Statistical Power ≥ 0.8 to detect meaningful Slide Courtesy G Sachs difference at p<.05 Effectiveness of Adjunctive Antidepressant Treatment for Bipolar Disorder

NS 30 27 25 23.5

20 MS + AD 15 NS 11 MS Alone 10 % Patients 10

5

0 Durable Recovery Switch Rates

Sachs GS et al. NEJM 2007; 356(17) Antidepressants in Bipolar Depression

• Adjunctive ADs may be helpful if prior history of response • Avoid use if patient with 2 or more concomitant core manic sxs, in presence of psychomotor agitation or rapid cycling. • Maintenance use of AD may be considered if patient relapses into depression after stopping AD therapy.

Pachioratti et al. ISBD Task Force on ATD Use in BP. Am J Psych.2013 Antidepressants in Bipolar Depression

• Switch rates: 10-20% (?) • Unclear if adjunctive mood stabilizers are protective. • Use SNRIs and TCAs second line, as they may promote more cycling/switches

Pachioratti et al. ISBD Task Force on ATD Use in BP. Am J Psych.2013 Psychotherapy by (buy) the Book Attention Deficit Hyperactivity Disorder Adult Attention Hyperactivity Disorder

• Chronic neurobehavioral disorder • Onset before age 7 • Inattention and/or hyperactivity/impulsivity • Clinically significant impairment in 2 or more settings (e.g. work, home, social settings) • Prevalence children 3-7% • Prevalence adults 4.4%

Kessler RC et al. Am J Psych 2006 Frequency of Symptom Subtype Among 536 Adult Patients with ADHD

Combined Inattentive Hyperactive/Impulsive 2% • Hyperactivity often diminishes with age (subjective, internal experience)

• Compensatory mechanisms develop over time 31% • Lack of recall of earlier problems

67%

Michelson D et al. Biol Psych 2003; 53:112-120 Adult Presentations of ADHD

• Difficulty with concentration/staying focused • Hyper-focus (focus in interesting, unimportant tasks) • Disorganization (procrastination, time- management) • Hyperactivity • Impulsivity • Emotional difficulties

These symptoms lead to…

• Relationship difficulties – Increased risk of divorce • Work difficulties – Increased risk of unemployment • Poor driving history • Psychological distress – Depression – Anxiety • Increased risk of incarceration

Wilens, T.E., Faraone, S.V., & Biederman, J. (2004). Attention- deficit/hyperactivity disorder in adults. The Journal of the American Medical Association, 292,619–623. Psychiatric Conditions Commonly Comorbid with Adult ADHD

Disorder Type Frequency of Comorbidity, %

Anxiety disorders 25-50 Mood disorders 19-37 Antisocial disorders 18-28 Personality disorders 10-20 Alcohol abuse 8-32 Other substance abuse 32-53

Baron DA. JCP Visuals vol 6, No. 3 June, 2004 Diagnostic Algorithm for Adult Does patient have historyADHD of childhood impulsive/hyperactive and/or inattentive behavior? No Yes Look for other Does patient have No significant functional Dxs impairment? Patient does not meet Yes DSM-IV criteria for ADHD Rule out other psychiatric disorders and rule in ADHD

Yes

Decide whether ADHD coexists with another psychiatric disorder

No Yes

Implement Treat both disorders, treatment plan for managing the most ADHD impairing first

Based on Barkley RA. Attention-Deficit Hyperactivity Disorder. 1998 and Baron DA. J Clin Psych June, 2004

Screens for Adult ADHD

• Not stand-alone agents for diagnosis • Collateral information helpful. • Recall of childhood symptoms may be inaccurate. • Checklists do not determine if other diagnoses my be cause of ADHD. symptoms. ADHD Rating Scales Used for Adults

Name Informant Rating Criteria

Connors’ Adult ADHD Self and/or DSM-IV Rating Scales observer

Wender Utah Rating Self Items from Minimal Scale Brain Dysfunction in Children

Brown ADD Rating Self Series of sx descriptors Scale for Adults reported by HS & college students with non hyper- active ADD

Adult ADHD Self-report Self DSM-IV-TR Scale-v1.1 Symptom Checklist for Adults 4 or more in shaded area highly consistent with adult ADHD

Symptom Checklist (no scoring) Treatment and Monitoring

1. Stimulants (methylphenidate, mixed amphetamine salts) 2. Atomoxetine* 3. Buproprion* † 4. Modafinil † • Face-to-face monthly until consistent optimal response. Then q 3-6 months. – Monitor heart rate, BP, weight. – Monitor adherence, abuse

* Black box warning re suicidality † not FDA-approved for treatment of ADHD Key Articles

Insomnia • Buysse DJ. Insomnia. JAMA. 2013; vol 309(7): 706-716

ADHD • Weiss MD et al. A guide to the treatment of adults with ADHD. J Clin Psych.2004; 65(suppl 3): 27-37 • Handout on stimulants Key Articles

Major Depression & Bipolar Disorder • Rothberg B & Schneck CD. Anxiety and Depression. In Textbook of Family Medicine, 8th Edition, Chapter 47, p 1060-1077. Rakel R and Rakel D. Elsevier Press, Philadelphia, 2011. (9th edition currently in press)

Questions?