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: •National Institute for Mental Health •Crown Family Foundation

Salary Support: •Ryan White HIV/AIDS Funding

Speakers Bureau: •None

Consulting: •None

Consulting Fees: •None

Stock Holdings (>$10,000) •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! • Initial relief of insomnia,

improved therapeutic alliance,

• Mood stabilizing

• Issues of physical and psychological dependence

• Insidious effects of long-term alteration of sleep architecture

• Tolerance, rebound • Abuse, falls, memory,

MVAs • Sleep eating/walking

+ _

FDA-Approved Medications for Insomnia

Unknown Mechanism •Chloral Hydrate

Antihistamine •Diphenhydramine •Doxylamine

Barbituate •Pentobarbital •Secobarbital •Butalbital

Benzodiazepines •Estazolam (ProSom) •Flurazepam (Dalmane) •Quazepam (Doral) •Temazepam (Restoril) •Triazolam (Halcion)

Benzodiazepine Receptor Agonists •Zolpidem (Ambien) •Zaleplon (Sonata) •Eszopiclone (Lunesta)

Melatonin Receptor Agonist •Ramelteon (Rozerem)

Orexin Antagonist • Suvorexant (Belsomra)

Tricyclic Antidepressant •Doxepin

Non-FDA Approved Medications for Insomnia

Anxyiolytic Benzodiazepines • Clonazepam • Alprazolam • Diazepam

Atypical Antipsychotics • Quetiapine (Seroquel) • Olanzapine (Zyprexa)

Antidepressants • Trazodone • Mirtazapine (Remeron) • Amitriptyline

Melatonin Receptor Agonists • Melatonin

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

Action Half-life Dose Indication

Triazolam (Halcion)

Short 2-5 0.125-0.25 mg Onset

Estazolam (Prosom)

Intermediate 10-24 0.5-2 mg Maintenance

Temazepam (Restoril)

Intermediate 8-15 7.5-30 mg Maintenance

Lorazepam* (Ativan)

Intermediate 8-12 1-2 mg Maintenance

Quazepam (Doral)

Long 50-200 (active metabs)

7.5-15 mg Maintenance

Flurazepam (Dalmane

Long 35 15-30 mg Maintenance

Clonazepam* (Klonopin)

Long 35 0.5-1 mg ?????

*Not FDA approved for insomnia

Benzodiazepine-Receptor Agonists

Medication Duration of Action

Half-life (hr) Dose Indications

Zaleplon (Sonata)

Ultra-short 1 5-20 mg Onset/ Maintenance*

Zolpidem (Ambien)

Short 3 5-10 mg Onset

Zolpidem CR (Ambien CR)

Short (80% initial release, 20%

delayed)

6.25-12.5 mg Maintenance

Eszopiclone (Lunesta)

Intermediate 5-7 1-3 mg Maintenance

*For maintenance, given on waking during the night

Melatonin Receptor Agonists

Medication Duration of Action

Half-life (hr) Dose Indications

Melatonin Ultra-short 30-50 Mins 0.3-5 mg (>1 mg supra-physiologic)

Sleep onset, circadian rhythm shifting

Remelteon (Rozerem)

Short 2-5 8 mg Onset

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 agonists

Have been associated w/ 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

• 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.

Online interventions appear efficacious

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

0

2

4

6

8

10

12

14

16

1950s Present

DepressionSchizophreniaHeart Dz

# o

f Mec

hani

stic

ally

Dis

tinct

Dru

gs

Insel TR & Scolnick EM. Mol Psych (2006) 11, 11-17

Antidepressants

SSRI Fluoxetine Paroxetine Sertraline Citalopram Escitalopram Fluvoxamine Vilazodone*

SNRI Venlafaxine Desvenlafaxine Duloxetine Levomilnaciprin

Mirtazapine Buproprion Trazodone Vortioxetine (Nefazodone)

Other TCA Amitriptyline Nortriptyline Desipramine Imipramine Doxepin Trimipramine Protriptyline Amoxapine

MAOI Phenelzine Selegeline (transdermal) Tranylcypromine Isocarboxazid

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

Slide courtesy M. Thase Depression Guideline Pane. AHCPR Publication 93-0550. 1993 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

SSRI + bupropion

+ mirtazapine

SNRI + bupropion

+ mirtazapine

SNRI + mirtazapine + bupropion Little Reason: SSRI + SSRI

SNRI + SNRI

Remission & Response Rates in CO-MED

0

10

20

30

40

50

60

12 Weeks Acute Phase

7 Months Continuation Phase

ESC + PCB

Remission

Response

BUP SR + ESC

Remission

Response

VFX XR + MIR

Remission

Response

Rush AJ et al.am J Psych 2011;168:689-701

Remission & Response Rates in CO-MED

0

10

20

30

40

50

60

12 Weeks Acute Phase

7 Months Continuation Phase

ESC + PCB

Remission

Response

BUP SR + ESC

Remission

Response

VFX XR + MIR

Remission

Response

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: One Illness, or Many?

Prevention

Stabilize from Above

Stabilize from Below

FDA-Approved Therapies for Bipolar Disorder

Therapy Bipolar Mania

Bipolar Depression Maintenance

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

0

10

20

30

40

50

60

70

80

90

100 Acceptability Efficacy

Cipriani A et al. Lancet Oct, 2011.

87 79

75 68

62 59 50

43 41 39

23 21

7 3

Treatment of

Bipolar Depression

Lurasidone Monotherapy Trials: Responder & Remitter Analysis

30%

25%

53%

42%

51%

40%

0%

10%

20%

30%

40%

50%

60%

Pro

port

ion

of P

atie

nts

Responders Remitters

PCB N=162

LUR 20-60 mg

N=161

LUR 80-120 mg

N=162

PCB N=162

LUR 20-60 mg

N=161

LUR 80-120 mg

N=162

** p<.01 *** p<.001

*** ***

** **

Loebel A et al. ICBD, 2013

Effect Size LUR 20-60 mg: 0.51

LUR 80-120 mg: 0.51

Observed Magnitude of Antidepressant Effect

1.1

0.4

0.9

0.3

0.7 0.7 0.65

0.51

0.3

0

0.2

0.4

0.6

0.8

1

1.2

Effect size (ES) = improvement over placebo/pooled SD. small < 0.4 moderate 0.4–0.79 large > 0.79.

Adapted from Calabrese JR. presented at: APA 2005 Annual Meeting, 2005 Atlanta, GA.

Effe

ct S

ize

QUE 600

QUE 300

LTG 200

OFC LTG 50

LUR 80- 120

OLZ QUE 600

QUE 300

Bipolar I

Bipolar II

QUE=quetiapine LTG=lamotrigine OFC=olanzapine/ fluoxetine LUR=lurasidone OLZ=olanzapine

Positive Antidepressant Trials with Adequate Sample Size* in Bipolar Depression

*Statistical Power ≥ 0.8 to detect meaningful difference at p<.05

Slide Courtesy G Sachs

Effectiveness of Adjunctive Antidepressant Treatment for Bipolar Disorder

23.5

10

27

11

0

5

10

15

20

25

30

Durable Recovery Switch Rates

% P

atie

nts

MS + ADMS Alone

Sachs GS et al. NEJM 2007; 356(17)

NS

NS

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

67%

31%

2% Combined Inattentive Hyperactive/Impulsive

Michelson D et al. Biol Psych 2003; 53:112-120

• Hyperactivity often diminishes with age (subjective, internal experience)

• Compensatory mechanisms develop over time

• Lack of recall of earlier problems

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 ADHD Does patient have history of childhood impulsive/hyperactive

and/or inattentive behavior?

No Yes

Look for other Dxs

Does patient have significant functional

impairment?

Rule out other psychiatric disorders and rule in ADHD

Yes

Yes

Decide whether ADHD coexists with another psychiatric disorder

Yes Treat both disorders, managing the most

impairing first

Implement treatment plan for

ADHD

No

No

Patient does not meet DSM-IV criteria for

ADHD

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?