number of patients per provider - internal medicine …...5-10 mg onset zolpidem cr (ambien cr)...
TRANSCRIPT
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?