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UPDATE IN PSYCHIATRY
Robert K. Schneider, MD
James L. Levenson, MD
Departments of Psychiatry and Medicine
The Medical College of Virginia at
the Virginia Commonwealth University
Richmond, Virginia
Previous Updates
Annals: October 1999
Annals: March 2001
Annals: February 2002
TOPICS COVERED –
• Mood Disorders
• Anxiety Disorders
• Medical-Psychiatric Interface
• Cognitive Disorders
MOOD DISORDERS
Which SSRI is works best?
Zoloft
citalopram
fluoxetine
Paxil
paroxetine
sertraline
Celexa
Prozac
SSRIs Compared in
Primary Care
Kroenke, JAMA 2001;286:2947
• Many claims of differences in efficacy
• ARTIST:
– A Randomized Trial Investigating SSRI Treatment
• Aim:
– Compare the effectiveness of 3 SSRIs in
depressed primary care patients.
SSRIs in Primary Care
• Methods
– RCT of paroxetine, fluoxetine and sertraline
– 573 patients, in 2 primary care consortiums
• Main Findings
– No statistical differences between the 3 SSRIs
in any of the outcomes.
100%
80%
60%
40%
20%
0%
Sertraline Paroxetine Fluoxetine
Recovery Rate
84%
81%
77%
Completers
43%
41%
50%
SSRIs in Primary Care
• Limitations
– Therapy based on MD perception
– 74% met diagnostic criteria for major
depression at baseline
– Low power for small differences
– No placebo control
– Mostly female (80%) and white (80%)
– No citalopram
Impact on clinical practice
• Efficacy not a basis for choosing SSRI
• Consider instead:
– Comorbidities
– Half-life
– Side effects
Which came first, the depression or
the erectile dysfuction?
Erectile Dysfunction and
Depression
Seidman, Am J Psych 2001;158:1623
• Depression and erectile dysfunction
occur often together in men, but the
causal relationship is unclear.
• Aim:
– Evaluate sildenafil in men with erectile
dysfunction and mild depression
Erectile Dysfunction and
Depression
• Methods
– RCT, double bind, placebo controlled
– Mild depression only
• Main Findings
– All measures of sexual function improved
significantly more in the sildenafil group (p<.001).
– Treatment-responders (48/66 given sildenafil, 10/70
given placebo) had significant improvements in
depression symptoms and quality of life compared
to nonresponders
Erectile Dysfunction and
Depression
• Limitations
– ? generalizable to patients with major
depression or taking psychotropic medications
– 12 week trial
Impact on clinical practice
• Treating physical symptoms in patients
with minor depression relieves depressive
symptoms.
– Erectile dysfunction
– Insomnia
– Pain
Is St. John’s wort an effective
antidepresant?
St. John’s Wort
Shelton, JAMA 2001; 285:1978
• Background:
– Many controlled trials of St. John’s wort claim
efficacy for the treatment of depression, but
they are methodologically flawed.
• Aim:
– To compare the efficacy and safety of St.
John’s wort vs. placebo in major depression
St. John’s Wort
• Methods
– RCT, double-blind, placebo-controlled
– 200 patients received either St. John’s wort
or placebo for 8 weeks.
• Main Findings
– No significant differences in any outcome
measures between the two groups
– St. John’s wort: 1% discontinued due to
adverse effects
St. John’s Wort
• Limitations
– Subjects had chronic depression (average
over 2 years)
– Subjects from tertiary care clinics
Impact on clinical practice
• St. Johns wort probably safe in minor
depression
• Caution with interactions with other drugs
– warfarin, cyclosporine, theophylline, digoxin,
protease inhibitors, anticonvulsants, oral
contraceptives, triptans, SSRIs
• Not a good choice for severe depression
Is estrogen an antidepressant in
menopausal women?
Estradiol for depression
Novaes Soares, Arch Gen Psych 2001;58:529
• Depressive and somatic symptoms are common in
women entering menopause.
• Studies of ERT for mood symptoms are complex
and have shown mixed results.
– Estrogen preparation: oral vs. transdermal
– Longitudinal measurements of estradial
– Endocrine confirmation of perimenopause: FSH
– Measurement of mood symptoms
– Placebo control difficult
Estradiol for depression
• Aim
– Assess efficacy of transdermal ERT for treating
depression in perimenopausal women.
• Methods
– RCT, double-blind, placebo-controlled
– FSH > 25 IU/L
– Depressive disorder (i.e. major depression,
dysthymia or minor depression)
– 17β-estradiol (100μg) transdermal patches or
placebo for 12 weeks and 4 week washout.
Estradiol for depression
Main Findings
– Remission of depressive symptoms in 68% vs. 20%
(P=0.001)
– no significant differences in response per type of
depressive disorder
– 50% reduction in menopausal symptoms was seen in
68% vs. 28% (P=0.005).
Limitations
– Small, short study in specialty clinic
– No progesterone
MADRS
Depression
25
20
15
Estradiol
Placebo
10
5
0
Baseline Week 4
BKMI
30
Perimenopausal
Symptoms
20
Week 8 Week 12 Week 16
25
15
Estradiol
Placebo
10
5
0
Baseline Week 4
Week 8 Week 12 Week 16
Impact on clinical practice
• Treatment with transdermal estrogen
patches is effective for depressive
symptoms in some perimenopausal women.
• This represents a good first step in
treatment of the depressed perimenopausal
women
• If symptoms persist or worsen, then
consider the addition of an antidepressant
How often do depressed patients
turn out to be bipolar?
Conversion from unipolar to
bipolar depression
Goldberg, Am J Psychiatry 2001;158:1265
• Background
– Underdiagnosis of bipolar disorder
– 20% of Major Depression may be bipolar
– Prescription of antidepressants without mood
stabilizers may precipitate a switch to mania
Unipolar to bipolar depression
• Aim
– In patients presenting with depression,
what are the odds they will turn out to
really be bipolar?
• Methods
– Young (mean 23 years), hospitalized
patients with depression
– Followed prospectively for 15 years
Unipolar to bipolar depression
• Main Findings
– 41% developed either hypomania or mania
(26% hypomania, 15% mania).
– 80% of the 10 patients who were initially
psychotic developed hypomania (4/10) or
mania (4/10).
– 34% of the non-psychotically depressed
eventually became either manic or hypomanic
What’s the differnece between
mania and hypomania?
• Mania (Bipolar I):
– At least 7 days of racing thoughts,
sleeplessness, grandiosity and
sometimes psychosis
• Hypomania (Bipolar II)
– At least 4 days of racing thoughts,
irritability, and sleeplessness
MANIA
MIXED EPISODE
HYPOMANIA
NORMAL
MOOD
DEPRESSION
5-5
Stahl S M, Essential
Psychopharmacology (2000)
Unipolar to bipolar depression
• Limitations
– Started in the early 1980s
• psychiatric hospitalization differs
• treatments differ
– Psychiatric inpatients
– Naturalistic study and not a treatment
intervention
Impact on clinical practice
• Younger patients with depression especially
with psychotic features may be at a particularly
high risk for conversion to bipolar depression.
• Remember that antidepressants may
precipitate switch to mania.
• “Side Effects” to antidepressants may
represent hypomania or mania
• Screen for mania/hypomania BEFORE
starting an antidepressant
How good is the care given for
depression and anxiety disorders?
Quality of Care for Depression
and Anxiety Disorders
Young, Arch Gen Psych 2001;58:55
• Depressive and anxiety disorders are
common, and cause substantial disability.
• Medications and psychotherapies have
empirically demonstrated efficacy
• BUT many patients do not receive adequate
treatment
Quality of Care
• Aim
– To estimate the rate of appropriate treatment
of anxiety and depressive disorders
– Measure effects of insurance, provider type,
and demographics
• Methods
– One year of data, from the National
Comorbidity Survey (1997-98)
Quality of Care
One year, adults, major anxiety or depression
• Main Findings:
– 83% saw a health care provider
– 30% received some appropriate treatment
– Most only saw PCP’s; 19% received appropriate care.
– 90% visiting MH professionals received appropriate
care.
– Insurance status affected whether the individual saw
a provider, but had no effect on whether appropriate
care was received.
Quality of Care
One year, adults, major anxiety or depression
• Main Findings:
– Appropriate treatment was less likely for
• men
• blacks
• the less educated
• those <30 or >59 years old
– When a psychiatric medication was used, it was at an
appropriate dose and duration in about 75% of the
individuals.
Quality of Care
• Main Findings:
– For patients seeing PCPs, those who received
poor quality care were less likely to report that…
• their mental health problems were evaluated
• psychiatric drugs were recommended
• referral to a mental health specialist was made
– Patients who received poor quality care were less
likely to view themselves as needing mental health
care (31.4% vs. 70%)
Impact on clinical practice
• Limitations
– Self report data, response rates
• Conclusions
– Most adults with depression or anxiety disorders did
not receive appropriate treatment, though they saw
health care providers
– When given, psychiatric medications were usually
given at appropriate dosage and duration.
– The current barriers to appropriate treatment lie in
recognition, diagnosis, referral, and acceptance by
patients.
ANXIETY DISORDERS
What are the psychiatric
consequences of a terrorist
disaster?
“The most severe incident
of terrorism ever
experienced on American
soil.”
Psychiatric Disorders Among
Survivors of the Oklahoma
City Bombing
North, JAMA 1999; 282:755
• Sometimes difficult to distinguish normal from
pathological reactions
• Aim
– Assess the psychiatric impact on adult survivors
directly exposed to the bomb blast.
Oklahoma City Bombing
• Methods
– Single diagnostic interview
• Main Findings
– 87% reported injuries
– Predisaster (lifetime) prevalence vs
postdisaster prevalence:
• PTSD [15% vs. 34%]
• Major Depression [12.6% vs. 22.5%]
Oklahoma City Bombing
• Main Findings:
– Postdisaster, 74% of PTSD and 56% of
major depression was new.
– Conversely, 71% of those with no
predisaster psychiatric diagnosis remained
without a postdisaster diagnosis
Oklahoma City Bombing
• Main Findings:
– Over 80% of the survivors had intrusive
reexperiences or hyperarousal symptoms.
– Only 34% of survivors had all three criteria
(including avoidance) for PTSD.
– Avoidance/numbing criterion was 100%
sensitive for detecting PTSD.
Oklahoma City Bombing
• Limitations
– Retrospective; direct exposure only
• Conclusions
– PTSD and Major Depression were the major
psychiatric disorders
– Hyperarousal and reexperiences common
– Avoidance/numbing screens for full PTSD
Impact on clinical practice
• Health predicts health
• Terror trauma uncommon,
sudden death of a loved one is not
• PTSD is very treatable
– Medications
– Psychotherapy
What’s the best initial drug
treatment for panic disorder?
Early Coadministration of
Benzodiazepines and SSRIs
Goddard, Arch Gen Psych 2001;58:681
• SSRIs are indicated for all anxiety
disorders
• But response to SSRIs is delayed
• Psychiatrists often start benzodiazepines
with SSRIs, but few controlled trials
Short vs. Longer
Acting Benzodiazepines
• Short acting benzodiazepine (alprazolam) seems
like a good choice (rapid onset of action)
– BUT is bad (rebound anxiety, euphoria, difficult to taper)
• Clonazepam is a intermediate half-life
benzodiazepine with a slower onset of action
– Early symptom reduction without euphoria
– Easily tapered
– Also, few active metabolites
Early Benzodiazepines
and SSRIs
• Aim
– Test the efficacy of early coadministration of
clonazepam and sertraline in panic disorder
• Methods
– 12 week, RCT
– Open-label sertraline
– Blinded to clonazepam 0.5mg TID or placebo
– Three week clonazepam taper at week 4
Early Benzodiazepines
and SSRIs
• Main Findings:
– Response rates:
• Week one (41% vs. 4%)
• Week three (63% vs. 32%)
– At end of trial, both groups’ response rates
were over 70%.
– No differences in secondary measures
between groups (i.e. drop out rates,
adverse reactions).
Early Benzodiazepines
and SSRIs
• Limitations
– Small group size
– 100 mg of sertraline may be more than needed
– May titrate slower
• Conclusions
– Rapid stabilization of panic disorder can be
achieved with early coadministration of sertraline
and clonazepam
Impact on clinical practice
• Panic disorder is common in the primary care
setting.
• A common practice used by psychiatrists that
could easily be used by non-psychiatrists in
the early treatment of panic disorder.
• Intermediate-acting benzos have advantages
over short-acting ones
MEDICAL-PSYCHIATRIC
INTERFACE
Can medication-induced
depression be prevented?
Interferon and Treatment of
Depression
Musselman, N Engl J Med 2001; 344:961
• Background
– Depression is the most frequent adverse effect
leading to discontinuation of interferon
– Interferons are important in the treatment of:
hepatitis C, multiple sclerosis, and malignancies
– Antidepressants effective in treating interferoninduced depression
Interferon and Depression
• Aim
– Will pretreatment with antidepressants reduce
depressive symptoms following interferon?
• Methods
– RCT, placebo controlled
– 2 week pretreatment with paroxetine before
interferon alpha for malignant melanoma
Interferon and Depression
• Major findings:
– Major depression (paroxetine vs. placebo):
11% vs. 45%
– Severe depression led to discontinuation of
interferon (paroxetine vs. placebo):
5% vs. 35%
– In the placebo group, if major depression,
then 78% discontinued interferon
Interferon and Depression
• Conclusions
– Pretreatment with paroxetine appears
effective in preventing depression induced
by interferon alfa in malignant melanoma
• Limitations
– Generalizable to other interferons and
diseases?
Impact on clinical practice
• Vital drugs may cause depression
e.g.interferons, steroids, betablockers, isotretinoin
• When it is not possible to substitute an
alternative medication, then:
– try treating the drug-induced depression with
antidepressants
– consider prevention before administering the
drug
What’s the risk of sudden cardiac
death with antipsychotics?
Antipsychotics and QTc
Prolongation
Ray, Arch Gen Psych 2001;58:1161
• Background
– Case reports have linked antipsychotic drugs with:
QTc prolongation, torsades de pointes, and sudden deaths
– “Black box” warnings regarding these risks added to
PDR for the older antipsychotics thioridazine and
mesoridazine
– Sertindole (new antipsychotic), was not registered in
the U.S. because it caused QTc prolongation and
sudden death
Antipsychotics and QTc
• Aim:
To determine the risk of sudden cardiac
death in antipsychotic users.
• Methods:
Retrospective cohort study of Tennessee
Medicaid enrollees
Antipsychotics and QTc
• Main Findings:
Corrected Risk Ratios:
– Moderate-dose antipsychotic use vs. nonuse: 2.39
– Low-dose antipsychotic use vs. nonuse: 1.30
– Moderate-dose antipsychotic use vs. nonuse in
patients with severe cardiovascular disease : 3.53
Antipsychotics and QTc
• Limitations
– Cannot determine causality
– Era before atypical antipsychotics
– Smoking and obesity not controlled for
– Sudden Death may be first symptom of CAD
• Conclusions
– Relative and absolute increases in the risk of
sudden death in patients taking moderate
doses of antipsychotics
Impact on clinical practice
• If prescribing an antipsychotic, take a
careful history for syncope or family history
of sudden death
• Patients at high risk should have
pretreatment EKG and receive
antipsychotics not shown to increase QTc
(olanzapine, risperidone, quetiapine)
Does group therapy prolong life in
metastatic breast cancer?
Group Therapy and Breast
Cancer
Goodwin, N Engl J Med. 2001;345:1719
• Background
Group therapy has been reported to provide
benefits for metastatic breast cancer,
including improvement in mood, pain control,
and in some but not all studies, survival.
Group Rx and Breast Cancer
• Aim
– To assess whether group therapy influences
survival, mood, and pain in women with
metastatic breast cancer
• Methods
– Multi-center randomized trial of supportiveexpressive group therapy
– Group therapy consisted of weekly 90-minute
sessions for at least one year
– All received routine care
Group Rx and Breast Cancer
• Main Findings:
– Greater improvements in psychological symptoms and
pain control (p=0.04) in the intervention group
– These benefits occurred in those women who were
more distressed at baseline.
– Did not prolong survival compared to routine care
alone (17.9 vs. 17.6 months)
• Limitations
– Only 9% of eligible women were randomly assigned
Impact on clinical practice
• Conclusions
– Many support groups are available
– Some women do not want to participate
– But increased survival is “proven” so they
may feel obligated to join
– Patient can be reassured that groups
improve pain control and mood but do not
prolong survival
COGNITIVE DISORDERS
Does cognitive function decline
after CABG?
Cognition after CABG
Newman, N Eng J Med 2001;344:395
• Background
– Perioperative cognitive decline after CABG
appears to be greatest at discharge.
– Cognition gradually improves for most patients
over next 6 months.
– But a significant number (10-30%) continue to
decline
• Aim
– To prospectively assess cognitive functioning
before and after CABG for five years
Cognition after CABG
• Methods
– Neurocognitive testing was performed before
surgery, at discharge, 6 weeks, 6 months and 5
years after CABG
• Main Findings
– Incidence of cognitive decline:
• 53% at discharge
• 36% at six weeks
• 24% at six months
• 42% at five years
Cognition after CABG
• Main Findings (cont)
– Most returned to baseline functioning
within 6 months.
– However, at 5 years, the patients with
cognitive decline at discharge had a
marked decline from their baseline
functioning (P<0.001); the patients without
cognitive decline at discharge did not.
Cognition after CABG
• Limitations
– Selective attrition may underestimate cognitive
decline
• One third of sample not available for long term followup
were more likely to have had complex disease
– Some cognitive decline due to illness not CABG
• Conclusions
– Patients with cognitive decline immediately after
elective CABG are at increased risk for long-term
cognitive decline
Impact on clinical practice
• Prior to elective CABG, the potential for
cognitive decline should be discussed :
– Cognitive decline is common
– Most improve over the first six months
– But a significant number will have impairment
at five years post-operatively
– This is one quality of life factor among others
• Especially important in the elderly
Is there a quick way to screen
for dementia?
Mini Cog: New, Easy-to-use
Screening Test for Dementia
Scanlan, Int J Geriatr Psych 2001;16:216
Borson, Int J Geriatr Psych 2000;15:1021
Background
• Screening for cognitive disorders has usually
been with the Mini Mental Status Exam
(MMSE).
– Hard to remember and time consuming.
– Research tool NOT a screening tool
Mini Cog Screen for Dementia
• Background (cont)
The Mini-Cog has just:
 the 3-item recall from the MMSE
 the Clock Drawing Test (CDT)
Requests the subject to fill in the numbers on a predrawn
circle and then add the hands for a designated time.
• Aim
– To evaluate the Mini-Cog at case-finding for
cognitively impaired adults.
Mini Cog Screen for Dementia
• Methods
– Community dwelling subjects, seen at a
university memory clinic
– Completed the MMSE, CASI (Cognitive
Abilities Screening Instrument), and the
Mini-Cog.
– Expert raters performed the MMSE and
CASI and “naïve” raters performed the
Mini-Cog.
Mini Cog Screen for Dementia
SENSITIVITY
SPECIFICITY
MMSE
91%
92%
CASI
92%
96%
MINI-COG
99%
93%
Mini Cog Screen for Dementia
• Main Findings
– Concordance between naïve and trained raters
was >98% for normal, moderately and severely
impaired clock drawings.
– Concordance dropped to 60% in mildly impaired
clock drawings
• But assuming naive raters would score mildly impaired
clocks as normal
• Then the Mini-Cog sensitivity and specificity changed
little (97% and 95%).
Mini Cog Screen for Dementia
• Conclusions
– The Mini-Cog is a time-efficient, sensitive and specific
tool that effectively identifies patients with probable
dementia, even by naïve raters.
• Limitations
– Conducted in a university memory clinic
– The population screened by an internist would have a
lower incidence of dementia, increasing false positives
and lowering specificity.
Impact on clinical practice
• The Mini-Cog provides an effective first-stage
screening tool for detecting dementia.
• Trained staff (naïve raters) could easily perform
this in an office setting.
• Combining this first-stage screening with a
second stage caregiver brief interview probably
represents an efficient and effective system for
screening for cognitive impairment in the elderly.