Recognizing the Physical Symptoms of Depression

1
Recognizing the Physical Symptoms of Depression
Volume 2 Number 2 August 2004
2
Introduction Alan F. Schatzberg, M.D.
3
Physical Symptoms Common In Psychiatric Patients
Psychiatric Healthy Symptom Patients
() Subjects () Tiredness, lack of
energy 85 40 Headache, head pains 64 48 Dizziness
or faintness 60 14 Feeling of weakness in parts
of body 57 23 Muscle pains, aches,
rheumatism 53 27 Stomach pains 51 20 Chest
pains 46 14
Data from Kellner R, Sheffield BF. The one-week
prevalence of symptoms in neurotic patients and
normals. Am J Psychiatry 1973130102105
4
Why Focus on Physical Symptoms?

• A growing literature explores the mind-body
  connection in mental illness
• Depression may have physical causes and
  consequences (like appetite and sleep
  disturbance, fatigue, and chronic pain)
• The presence of physical symptoms in depression
  may affect response to treatment

5
How Chronic Pain Affects the Symptoms of
Depression Maurice M. Ohayon, M.D., D.Sc., Ph.D.
6
Patients With Major Depressive Disorder

• Report only physical symptoms in up to 69 of
  primary care cases1
• E.g.,insomnia or hypersomnia, psychomotor
  agitation or retardation, changes in appetite,
  fatigue
• Are at 4x greater risk than nondepressed patients
  for having a chronic painful physical condition
  (CPPC)2
• Are more likely than nondepressed patients to
  have long-term medical conditions3

1Simon GE, VonKorff M, Piccinelli M, et al. An
international study of the relation between
somatic symptoms and depression. N Engl J Med
199934113291335 2Ohayon MM, Schatzberg AF.
Using chronic pain to predict depressive
morbidity in the general population. Arch Gen
Psychiatry 2003603947 3Patten SB. Long-term
medical conditions and major depression in a
Canadian population study at waves 1 and 2. J
Affect Disord 2001633541
7
Influence of CPPCs on Depressive Symptoms

• Method
• General population respondents 15 years of age
• Total N 18,980 in 5 European countries
• Interviewed by telephone using several
  instruments
• Sleep-EVAL, DSM-IV, and International
  Classification of Sleep Disorders criteria,
  questions about painful physical conditions, and
  questions about psychological and physical
  symptoms of depression

Ohayon MM. Specific characteristics of the
pain/depression association in the general
population. J Clin Psychiatry 200465(suppl
12)59
8
Influence of CPPCs on Depressive Symptoms

• Results
• 17.1 of respondents with at least 1 CPPC
• 4.0 of respondents with major depressive
  disorder (MDD)
• Likelihood of either condition was higher among
  patients 25 and older and was higher among women

Ohayon MM. Specific characteristics of the
pain/depression association in the general
population. J Clin Psychiatry 200465(suppl
12)59
9
Prevalence of MDD by Presence of CPPC and Age
Groupa
aThe total of the 2 CPPC categories equals the
total prevalence of MDD for each age
group. Abbreviations CPPC Chronic Painful
Physical Condition, MDD Major Depressive
Disorder. Reprinted with permission from Ohayon
MM. Specific characteristics of the
pain/depression association in the general
population. J Clin Psychiatry 200465(suppl
12)59
10
Subjects With MDD Plus At Least 1 CPPC

• Represented 43.4 of subjects with MDD
• Had a longer duration of current depressive
  episode than depressed subjects without a CPPC
• 31.4 months vs. 24.3 months
• Were more likely to have had a past depressive
  episode than depressed subjects without a CPPC
• 24.4 vs. 17.4

Ohayon MM. Specific characteristics of the
pain/depression association in the general
population. J Clin Psychiatry 200465(suppl
12)59
11
Frequency and Severity of Depressive Symptoms in
Subjects With MDD and With or Without CPPC
With Without CPPC CPPC (N  330), (N  429),
OR Symptom (95 CI)
Feeling sad, depressed nearly every
day     Moderately 41.2 30.7 1.6 (1.2 to
2.1)     A lot/extremely 28.0 17.9 1.8 (1.3 to
2.5) Loss of interest in activities nearly every
day     Moderately 28.3 24.8 1.2 (0.9 to
1.7)     A lot/extremely 26.5 21.5 1.3 (0.9 to
1.8) Psychomotor agitation nearly every day
13.8 9.2 1.6 (1.0 to 2.5)     Moderately 7.9 5.4
1.5 (0.8 to 2.7)     A lot/extremely 5.9 3.8 1.6
(0.8 to 3.1) Psychomotor retardation nearly every
day     Moderately 14.1 10.2 1.5 (0.9 to
2.2)     A lot/extremely 7.7 2.5 3.3 (1.6 to
6.7) Weight loss 28.9 23.6 1.3 (0.9 to
1.8) Weight gain 21.3 10.4 2.3 (1.1 to
5.2) (cont.)
p lt .05, p lt .01, p lt .001 vs. patients
without CPPC. Abbreviations CPPC Chronic
Painful Physical Condition, MDD Major
Depressive Disorder. Ohayon MM. Specific
characteristics of the pain/depression
association in the general population. J Clin
Psychiatry 200465(suppl 12)59
12
Frequency and Severity of Depressive Symptoms in
Subjects With MDD and With or Without CPPC (cont.)
With Without CPPC CPPC (N  330), (N  429),
OR Symptom (95 CI)
Insomnia    34 nights/week 43.1 44.4 1.0 (0.7
to 1.3)   57 nights/week 31.1 12.2 3.3 (2.2
to 4.7) Hypersomnia    34 nights/week 8.2 10.5
0.8 (0.5 to 1.3)    57 nights/week 12.8 8.3 1.6
(1.0 to 2.6) Fatigue nearly every day   
Moderately 17.2 15.5 1.1 (0.8 to 1.7)    A
lot/extremely 13.0 2.7 5.4 (2.8 to
10.5) Feeling of worthlessness or guilt nearly
every day     Moderately 12.3 7.9 1.6 (1.0 to
2.6)     A lot/extremely 7.4 6.7 1.1 (0.6 to
1.9) Impaired concentration   
Moderately 16.5 11.9 1.5 (1.0 to 2.2)    A
lot/extremely 13.4 8.4 1.7 (1.1 to
2.7) Suicidal ideation 44.1 37.3 1.3 (1.0 to 1.8)
p lt .05, p lt .01, p lt .001 vs. patients
without CPPC. Abbreviations CPPC Chronic
Painful Physical Condition, MDD Major
Depressive Disorder. Ohayon MM. Specific
characteristics of the pain/depression
association in the general population. J Clin
Psychiatry 200465(suppl 12)59
13
Conclusions

• CPPCs were extremely common in subjects with MDD
• The presence of a CPPC statistically
  significantly increased the frequency and
  severity of 7 depressive symptoms
• Feeling sad or depressed, psychomotor agitation,
  psychomotor retardation, weight gain, insomnia,
  fatigue, and impaired concentration
• Some physical symptoms of depression may be
  attributable to chronic pain rather than
  depressive illness, but, conversely, physical
  symptoms may be due to MDD rather than chronic
  pain
• Clinician vigilance and discernment is necessary
  to determine whether physical symptoms indicate
  depression

14
Childhood Maltreatment and Adult Health and
Psychiatric Outcomes Bruce A. Arnow, Ph.D.
15
Prevalence Estimates of Childhood Maltreatment
Vary According to Study Methodology

• Definition of terms
• E.g., childhood and abuse
• Survey tactics employed
• E.g., mailed questionnaire, face-to-face
  interview
• Respondent population
• E.g., general public, primary care patients,
  psychiatric patients

16
Estimated Prevalence in the General Population

• Childhood sexual abuse1
• 8 to 32 in women
• 1 to 16 in men
• Childhood physical abuse2
• Approximately 20 in women and men

1Finkelhor D. Current information on the scope
and nature of child sexual abuse. Future Child
199443153 2Briere J, Elliot DM. Prevalence and
psychological sequelae of self-reported childhood
physical and sexual abuse in a general
population sample of men and women. Child Abuse
Negl 20032712051222
17
Higher Prevalence of Childhood Abuse in
Specialized Settings

• 44 of primary care patients reported sexual,
  physical, or emotional abuse as children1
• 53 of women in emergency psychiatric care
  reported childhood sexual abuse 42 reported
  childhood physical abuse2
• 55 of female psychiatric inpatients reported
  multiple types of childhood abuse3

1Gould DA, Stevens NG, Ward A, et al.
Self-reported childhood abuse in an adult
population in a primary care setting prevalence,
correlates, and associated suicide attempts. Arch
Fam Med 19943252256 2Briere J, Woo R, McRae B,
et al. Lifetime victimization history,
demographics, and clinical status in female
psychiatric emergency room patients. J Nerv Ment
Dis 199718595101 3Swett C, Alpert M. Reported
history of physical and sexual abuse in relation
to dissociation and other symptomatology in women
psychiatric inpatients. J Interpersonal Violence
19938545555
18
Adult Psychiatric Outcomes

• Childhood maltreatment is associated with adult
  psychiatric sequelae
• MDD, anxiety, substance abuse/dependence are
  especially common
• Greater severity, frequency, and number of types
  of maltreatment exacerbate risk
• In a community sample, childhood sexual abuse
  raised the rate of having at least 1 lifetime
  psychiatric disorder from 49 in women and 51 in
  men to 78 in women and 82 in men1

1Molnar BE, Buka SL, Kessler RC. Child sexual
abuse and subsequent psychopathology results
from the National Comorbidity Survey. Am J Pub
Health 200191753760
19
Association Between Childhood Sexual and/or
Physical Abuse and Adult Mental Health Symptoms
in Primary Care
p lt .001 vs. patients with no abuse. aHigh
upper 1/3 of score range on Symptom
Checklist-22 Data from McCauley J, Kern DE,
Kolodner K, et al. Clinical characteristics of
women with a history of childhood abuse unhealed
wounds. JAMA 199727713621368
20
Relative Risk of MDD Among Adults Who Report
Childhood Abuse Compared With Adults Who Do Not

• Physical abuse 2.4x greater
• Sexual abuse 1.8x greater
• Both physical and sexual abuse 3.3x greater

Wise L, Zierler S, Krieger N, et al. Adult onset
of major depressive disorder in relation to
childhood and adolescent violence victimization
a case-control study. Lancet 2001358881887
21
Significant Associations of the Relationship
Between Childhood Maltreatment and Adult MDD

• Earlier onset of MDD1
• High comorbidity and chronicity of MDD1,2
• Suicide attempts in adulthood3

1Bernet CZ, Stein MB. Relationship of childhood
maltreatment to the onset and course of major
depression in adulthood. Depress Anxiety
19999169174 2Brown GW, Moran P. Clinical and
psychosocial origins of chronic depressive
episodes, pt.1 a community survey. Br J
Psychiatry 1994165447452 3Bifulco A, Moran P,
Baines R, et al. Exploring psychological abuse in
childhood, pt. 2 association with other abuse
and adult clinical depression. Bull Menninger
Clin 200266241258
22
Physical Symptoms Linked to Childhood
Victimization

• Chronic pelvic pain1
• Fibromyalgia2
• Irritable bowel syndrome3
• Headache4

1Walker E, Katon W, Harrop-Griffiths J, et al.
Relationships of chronic pelvic pain to
psychiatric diagnoses and childhood sexual abuse.
Am J Psychiatry 19881457580 2Walker EA, Keegan
D, Gardner G, et al. Psychosocial factors in
fibromyalgia compared with rheumatoid arthritis,
pt. 2 sexual, physical, and emotional abuse and
neglect. Psychosom Med 199759572577 3Talley
NJ, Fett SL, Zinsmeister AR, et al.
Gastrointestinal tract symptoms and self-reported
abuse a population-based study. Gastroenterology
199410710401049 4Golding JM. Sexual assault
history and headache 5 general population
studies. J Nerv Ment Dis 1999187624629
23
Other Adult Health Outcomes Associated With
Childhood Maltreatment or Household Dysfunctiona
Correlated disease states1 Heart disease,
cancer, chronic lung disease, and liver
disease Increased health-risk behaviors Alcoholis
m/drug abuse,2 driving while intoxicated,2
irregular seatbelt use,2 risky sexual
behaviors,1,2 sedentary lifestyle,1,2 obesity,1,2
and cigarette smoking2
aE.g.,mental illness, imprisonment/criminality,
substance abuse, and/or violence. 1Felitti VJ,
Anda RF, Nordenberg D, et al. Relationship of
childhood abuse and household dysfunction to many
of the leading causes of death in adults. Am J
Prev Med 199814245258 2Walker EA, Gelfand A,
Katon WJ, et al. Adult health status of women
with histories of childhood abuse and neglect. Am
J Med 1999107332339
24
Medical Utilization

• Elevated among adults with depression1
• Elevated among adults with a history of childhood
  abuse2
• Higher among adults with psychological distress
  childhood sexual abuse than among adults with
  either condition alone3
• Higher still among adults with psychological
  distress sexual abuse physical abuse3

1Simon GE, VonKorff M, Barlow W. Health care
costs of primary care patients with recognized
depression. Arch Gen Psychiatry
199552850856 2Walker EA, Unutzer J, Rutter C,
et al. Costs of health care use by women HMO
members with a history of childhood abuse and
neglect. Arch Gen Psychiatry 199956609613 3Arno
w BA, Hart S, Hayward C, et al. Severity of child
maltreatment, pain complaints, and medical
utilization among women. J Psychiatr Res
200034413421
25
Conclusions

• Reported rates of childhood abuse are highest in
  psychiatric settings
• Childhood maltreatment is associated with
• Adult psychiatric sequelae, especially depression
• Both medically explained and unexplained physical
  symptoms, especially chronic pain
• Health-risk behaviors in adulthood
• A graded relationship between severity of
  maltreatment and adult outcomes including poor
  psychological outcomes, pain complaints, and
  medical utilization

26
The Nature of Depression and Its Treatment With
Dual-Acting Antidepressants Pedro L. Delgado,
M.D.
27
Recurrence of MDD

• 75 to 90 of people with depression will have
  multiple episodes1,2
• Each episode is more easily provoked than the
  last3
• Residual symptoms following recovery increase
  risk of recurrence4

1Angst J. How recurrent and predictable is
depressive illness? In Montgomery SA, Rouillon
F, eds. Long-Term Treatment of Depressive
Perspectives in Psychiatry, vol 3. Chichester,
England Wiley1992113 2Kupfer DJ. Long-term
treatment of depression. J Clin Psychiatry
199152(suppl 5)2834 3Kendler KS, Thornton LM,
Gardner CO. Stressful life events and previous
episodes in the etiology of major depression in
women an evaluation of the kindling
hypothesis. Am J Psychiatry 200015712431251 4Ju
dd LL, Akiskal HS, Maser JD, et al. Major
depressive disorder a prospective study of
residual subthreshold depressive symptoms as
predictor of rapid relapse. J Affect Disord
19985097108
28
Why Aim to Prevent Recurrence of Depressive
Episodes?

• Much of the burden of MDD is linked to its
  chronic nature1,2
• Episodes tend to become more frequent, severe,
  and treatment resistant over time3
• Number (and duration) of previous episodes may
  predict relapse3
• Prolonged depression and multiple episodes may
  cause brain damage (loss of hippocampal volume)4,5

1Angst J. How recurrent and predictable is
depressive illness? In Montgomery SA, Rouillon
F, eds. Long-Term Treatment of Depressive
Perspectives in Psychiatry, vol 3. Chichester,
England Wiley1992113 2Kupfer DJ. Long-term
treatment of depression. J Clin Psychiatry
199152(suppl 5)2834 3Keller MB, Boland RJ.
Implications of failing to achieve successful
long-term maintenance treatment of recurrent
unipolar major depression. Biol Psychiatry
199844348360 4Sheline YI, Sanghavi M, Mintun
MA, et al. Depression duration but not age
predicts hippocampal volume loss in medically
healthy women with recurrent major depression. J
Neurosci 19991950345043 5Bremner JD, Narayan
M, Anderson ER, et al. Hippocampal volume
reduction in major depression. Am J Psychiatry
200316015161518
29
Neurobiology of Depression Serotonin and
Norepinephrine

• Are part of the bodys endogenous analgesic
  system
• Play overlapping but divergent roles in
  depression
• Are involved in the etiology of some physical and
  emotional symptoms of depression
• Affect how medications work to treat depression
• Some beneficial effects of antidepressant
  treatment may be due to neurogenesis (cell
  growth) in affected areas of the depressed brain

30
Dual-Acting Antidepressants

• Overall, dual-acting agents appear to be more
  effective than single-acting agents in improving
  mood, reducing pain, and increasing the chance of
  remission
• Tricyclic antidepressant (TCA) imipramine induces
  neurogenesis even in mice genetically modified to
  have no 5-HT1A receptors1
• Serotonin-norepinephrine reuptake inhibitors
  (SNRIs) venlafaxine2 and duloxetine3 have reduced
  pain sensitivity in a dose-dependent manner in
  patients with diabetic neuropathy

1Santarelli L, Saxe MD, Gross C, et al.
Requirement of hippocampal neurogenesis for the
behavioral effects of antidepressants. Science
2003301805809 2Kunz NR, Goli V, Entsuah R, et
al. Diabetic neuropathic pain management with
venlafaxine extended release. Eur
Neuropsychopharmacol 200010(suppl
3)S389 3Goldstein DJ, Lu Y, Iyengar S, et al.
Duloxetine in the treatment of the pain
associated with diabetic neuropathy. Presented
at the 156th Annual Meeting of the American
Psychiatric Association May 1722, 2003 San
Francisco, Calif. Abstract NR1856869
31
Conclusions

• Early, aggressive, effective intervention in
  depression is recommended
• Dual-acting antidepressants that inhibit reuptake
  of both serotonin and norepinephrine treat a
  wider array of depressive symptoms (psychological
  and physical) than antidepressants that target
  either neurotransmitter alone

32
The Search for Better Outcomes in the Treatment
of Depression Vivien K. Burt, M.D., Ph.D.
33
Response and Remission

• Response to antidepressant treatment frequently
  falls short of remission
• Full remission is achieved more readily when the
  entire spectrum of depressive symptoms is
  targeted
• With medication (single-acting vs. dual-acting
  agents)
• With psychotherapy
• Some special populations (such as women) may
  respond preferentially to certain antidepressant
  classes

34
Dual- Versus Single-Acting Agents

• Combination of fluoxetine (serotonergic action)
  and desipramine (noradrenergic action) was more
  effective in treating depression than either
  agent alone1
• Dual-acting TCAs were more effective in treating
  depression than single-acting TCAs or selective
  serotonin reuptake inhibitors (SSRIs)24
• TCAs have a considerable side effect profile, can
  be lethal in overdose

1Nelson J, Mazure C, Jatlow P, et al. Combining
norepinephrine and serotonin reuptake inhibition
mechanisms for treatment of depression a
double-blind, randomized study. Biol Psychiatry
200455296300 2Anderson IM. SSRIs versus
tricyclic antidepressants in depressed
inpatients a meta-analysis of efficacy and
tolerability. Depress Anxiety 19987(suppl
1)1117 3Danish University Antidepressant Group.
Paroxetine a selective serotonin reuptake
inhibitor showing better tolerance, but
weaker antidepressant effect than clomipramine
in a controlled multicenter study. J Affect
Disord 199018289299 4Danish University
Antidepressant Group. Citalopram clinical effect
profile in comparison with clomipramine a
controlled multicenter study. Psychopharmacology
(Berl) 198690131138
35
Dual- Versus Single-Acting Agents

• Venlafaxine (SNRI) gt SSRIs1
• 9 of venlafaxine-treated patients discontinued
  treatment vs. 7 of SSRI-treated patients
• 45 of venlafaxine-treated patients achieved
  remission vs. 35 of SSRI-treated patients
• Mirtazapine (noradrenergic and specific
  serotonergic antidepressant) gt SSRIs2
• 13.4 of fluoxetine-treated patients discontinued
  treatment vs. 10.6 of mirtazapine-treated
  patients
• Reduction in Hamilton Rating Scale for Depression
  (HAM-D) scores from baseline was greater with
  mirtazapine than fluoxetine

1Thase ME, Entsuah AR, Rudolph RL. Remission
rates during treatment with venlafaxine or
selective serotonin reuptake inhibitors. Br J
Psychiatry 2001178234241 2Wheatley D, van
Moffaert M, Timmerman L, et al. Mirtazapine
efficacy and tolerability in comparison with
fluoxetine in patients with moderate to severe
major depressive disorder. J Clin Psychiatry
199859306312
36
Pain, Anxiety, and SNRIs

• Venlafaxine (at higher doses) and duloxetine may
  be especially efficacious in alleviating
  physical, anxious, and negative mood symptoms of
  depression
• Duloxetine showed a higher affinity than
  venlafaxine for serotonin and norepinephrine
  receptors1
• Compared with placebo, duloxetine significantly
  reduced overall HAM-D scores (p lt .001),2 somatic
  symptoms (p .013),2 pain (p lt .001),2 and
  anxiety (p lt .005)3

1Bymaster FP, Dreshfield-Ahmad LJ, Threlkeld PG,
et al. Comparative affinity of duloxetine and
venlafaxine for serotonin and norepinephrine
transporters in vitro and in vivo, human
serotonin receptor subtypes, and other neuronal
receptors. Neuropsychopharmacology
200125871880 2Detke MJ, Lu Y, Goldstein DJ, et
al. Duloxetine, 60 mg once daily, for major
depressive disorder a randomized double-blind
placebo-controlled trial. J Clin Psychiatry
200263308315 3Dunner D, Goldstein D,
Mallinckrodt C, et al. Duloxetine in the
treatment of anxiety symptoms associated with
depression. Depress Anxiety 2003185361
37
Duloxetine Versus Placebo in MDD
p lt .001 vs. placebo. Abbreviations HAM-D-17
17-item Hamilton Rating Scale for Depression, LS
least squares, MDD Major Depressive
Disorder, SNRI serotonin-norepinephrine
reuptake inhibitor. Reprinted with permission
from Detke MJ, Lu Y, Goldstein DJ, et al.
Duloxetine, 60 mg once daily, for major
depressive disorder a randomized double-blind
placebo-controlled trial. J Clin Psychiatry
200263308315
38
Symptoms of Somatic and Pure Depression by Sex
p lt .05 vs. patients with pure depression. Data
from Silverstein B. Gender differences in the
prevalence of clinical depression the role
played by depression associated with somatic
symptoms. Am J Psychiatry 1999156480482
39
Duloxetine Efficacy for Overall Pain in Women by
Age
p .043, p lt .001 vs. placebo. Reprinted with
permission from Burt VK. Plotting the course to
remission the search for better outcomes in the
treatment of depression. J Clin Psychiatry
200465(suppl 12)2025
40
Conclusions

• Dual-acting agents that modulate serotonin and
  norepinephrine are more effective than
  single-acting agents in treating the emotional
  and physical symptoms of depression
• Including pain
• Especially in women of perimenopausal age