Mood disorders

Rafat Alowesie,MD,MSc

Causes of GlobalBurden of Disease

2004• LRTIs• Diarrheal diseases• Unipolar depression• Ischemic heart disease• HIV/AIDS

2030• Unipolar depression• Ischemic heart disease• Road traffic accidents• Cerebrovascular disease• COPD

MDD = major depressive disorder; LRTI = lower respiratory tract infection; HIV = human immunodeficiency virus; AIDS = acquired immunodeficiency syndrome; COPD = chronic obstructive pulmonary disease1. World Health Organization. The Global Burden of Disease: 2004 Update. WHO; 2004.2. World Health Organization. World Health Organization Website. Mental Health. Depression. What is depression? Available at: http://www.who.int/mental_health/management/depression/definition/en/index.html, Accessed October 28, 2011.

MDD = major depressive disorder; LRTI = lower respiratory tract infection; HIV = human immunodeficiency virus; AIDS = acquired immunodeficiency syndrome; COPD = chronic obstructive pulmonary disease1. World Health Organization. The Global Burden of Disease: 2004 Update. WHO; 2004.2. World Health Organization. World Health Organization Website. Mental Health. Depression. What is depression? Available at: http://www.who.int/mental_health/management/depression/definition/en/index.html, Accessed October 28, 2011.

MDD:• 2004: #3 cause of global burden of

disease• 2020: #2 cause of global burden of

disease• 2030: #1 cause of global burden of

disease

Depression is not:

• “Weakness of character”

• “Madness”

• “Something that will pass”

• Incurable

• Inevitable

WHAT IS DEPRESSION?

• Persistent low mood for at least two weeks plus at least 5 of the following:

• poor appetite or weight loss or increased appetite or weight gain..

• Loss of energy or tiredness to the point of being unable to make the simplest everyday decisions.

• An observable slowing down or agitation.

Depression is …

• A markedly diminished loss of interest or pleasure in activities that were once enjoyed.

• Feelings of self-reproach or excessive or inappropriate guilt over real or imagined misdeeds.

• Complaints/evidence of diminished ability to think or concentrate.

• Recurrent thoughts of death, suicide, suicidal thoughts without a specific plan, or a suicide attempt or plan.

Depression is …

A - Appetite

S - SleepA - AnhedoniaD - Depressed mood

F - FatigueA - AgitationC - ConcentrationE - EsteemS - Suicidal

Montano, J Clin Psych 1994

DEPRESSION: A SAD FACE (S)

• Age: peak age of onset 20-40 yrs

• Gender: female 2 X higher

• Family history: 1.5 to 3 X higher

• Marital status: divorced, separated, widowed

• married vs. unmarried???

DEPRESSION: RISK FACTORS

• Personal history of depression1 episode - 50% relapse2 episodes - 75% relapse3 episodes - 90% relapse

• Postpartum: up to 1 in 10 women

• Chronic medical illness

DEPRESSION: RISK FACTORS

Functional Impairment in MDD

MDD impairs occupational and social functioning1,2

– 87% exhibit at least moderate impairment3

– 59% exhibit severe or very severe impairment3

MDD is associated with1:– Increased number of disability days– Decreased work productivity, psychosocial

disability

MDD and work productivity1

– Impact on function at work is substantially higher than missed work days

– Absenteeism represents only a small fraction of workplace cost1. Druss BG et al. Am J Psychiatry. 2001;731-34.

2. Judd LL, et al. Arch Gen Psychiatry. 2000;57:375-80.3. Kessler RC et al. JAMA. 2003;289:3095-105.

Etiology and Pathogenesis of

Depressive Disorders

• Biochemical: a deficit of specific neurotransmitters in the brain mainly Serotonin, Noradrenaline and Dopamine

• Psychosocial : factors like low self steem and dependant personalities

• Social: life events and stress

• Developmental factors: genetic and hereditary factors

• Integrative: involves all previous factors

Areas in Brain Affected by

Depression

• Limbic System

• Hypothalamus

DSM qualifiers of mood states ( coded with main diagnosis)

Atypical features Overeating, oversleeping while depressed; preserved reactivity to reward.

Catatonic Features Detachment from the environment while awake; negativism including immobility, mutism, refusal to eat or drink. May be life-threatening.

Melancholic Features

Dense anhedonia, lack of response to reward, terminal insomnia (early morning awakening), diurnal variation (mornings worse).

Postpartum onset Depressive episode within 1 month of childbirth by definition. Clinically, this period of markedly increased risk may be > 3 months. Often includes marked anxiety.

Psychotic features Mood congruent in depression: Delusions of poverty, guilt, nihilism, illness, self-disgust; derogatory auditory hallucinations.Mood congruent in mania: Delusions of special powers or unlimited resources, paranoia, auditory hallucinations.

A 21st Century View of Depression

Neurotransmission:neurotransmitters and

Neuropeptides and synaptic connectivity

BDNF = brain-derived neurotrophic factor; CREB = cAMP responsive element binding; HPA = hypothalamic-pituitary-adrenal; mRNA = messenger ribonucleic acid; PKC = protein kinase C;

Schloesser RJ et al. 2008. Neuropsychopharmacol Rev. 2008;33:110-33.

r

Early Life Adverse Events

Environmental factors(including external

environment:psychosocial

stressors, sleep deprivation, internal

environment: gonadal/HPA steroids)

BDNF, CREB, PKC, and other regulatory proteins

Gold PW, Charney DS. Am J Psychiatry. 2002;159(11):1826.

Depression: A Disease of the Mind, Brain, and Body

Major Depressive Disorder May Have Systemic Consequences

2Adrenal gland releases excessive amounts of catecholamines and cortisol

ACTH

1Hypothalamus stimulates pituitary gland to release excessive ACTH, continuously driving the adrenal gland

5 Cortisol antagonizes insulin and contributes to dyslipidemia

4Increase in catecholamines causes platelet activation; increase in cytokines and interleukins may also contribute to atherosclerosis and eventual hypertension

3Increase in catecholamines can lead to myocardial ischemia, diminished heart rate variability, and can contribute to ventricular arrhythmias

ACTH=Adrenocorticotropic hormoneAdapted from Musselman DL et al. Arch Gen Psychiatry 1998;55(7):580-92.

Depression and Chronic Disease

Chronic illness has been associated with increased prevalence of depressionDiseases include:– Diabetes– Hypertension– Cardiovascular diseases– Mild cognitive impairment prior to onset of

dementia– Cancer– HIV– COPD– Rheumatoid arthritis

HIV = human immunodeficiency virus; COPD = chronic obstructive pulmonary diseaseSimon GE. West J Med 2001;175:292-3; de Groot et al., Diabetes Spectrum 2010;23:15-8; Scalco AZ et al. Clinics 2005;60:241-50; Barnes DE et al. Arch Gen Psychiatry 2006;63:273-80; Lin HB et al. Ann Fam Med 2009;7:414-21.

39.0%

45.0%

47.0%

42.0%

33.0%

36.0%

33.0%

9.4%

5.8%

0% 10% 20% 30% 40% 50%

Parkinson's Disease

MI

Stroke

Cancer Inpatients

Cancer Outpatients

Older Inpatients

Hospitalized

Chronically Ill

General Population

Prevalence Rates of Depression in Chronic Medical Disorder

Martin Davis 1997

Depression

Decrease in neurogenesis

Cellular atrophy

Decrease in hippocampal volume

Frodl et al. Am J Psych. 2002; McKittrick et al. Synapse. 2000; Duman R. CNS Spectrum, 2002.

Structural changes in brain

in depression2000s

Cellular Atrophy in Depression

Rat hippocampal neurone before (A) and after (B) 3-week repeated stress

Evidence of Hippocampal Atrophy and Loss in Patients With MDD

1. Bremner JD, et al. Am J Psychiatry. 2000;157(1):115-118.2. Sheline YI, et al. J Neurosci. 1999;19(12):5034-5043.3. Sheline YI, et al. Proc Natl Acad Sci USA. 1996;93(9):3908-3913.4. Sheline YI, et al. Am J Psychiatry. 2003;160(8):1516-1518.

Images courtesy of JD Bremner.

• Compared to controls, patients with depression had smaller hippocampal volumes (n=16)1

• Decreased hippocampal volume may be related to the duration of depression2-4

Barriers to Diagnosis and

Treatment in the Arab countries

• Lack of education about depression

• Lack of availability of appropriate therapies

• Competing clinical demands

• Social issues

• Lack of patient acceptance of the diagnosis

Nasir LS, A-Qutob R. J Am Board Fam Pract 2005;18(2):125-31.

Freud

“ Melancholia, whose definition fluctuates even in descriptive psychiatry, takes on various clinical forms the grouping together of which into a single unity does not seem to be established with certainty; and some of these forms suggest somatic rather than psychogenic affections.”

Mourning and Melancholia (1917)

Are Depressed patients more likely to be medically ill?

• 1500 Depressed Patients were evaluated for General Medical Conditions

• Total prevalence was 53%

• Those with older age, Lower income, unemployment, limited education and longer duration of depression were at higher risk

Disease/ System

Prevalence %

Musculo skeletal

43%

Respiratory

32%

Heart 29%

Upper GI 26%

Neurological

25%

Endocrine 24%

27

Yates et al, Gen Hosp Psych 2004 STAR-D Study

Likelihood of Depression Increases

with No. of Physical Symptoms at

Presentation

0

10

20

30

40

50

60

70

0-1 2 to 3 4 to 5 6 to 8 >9

No. of Physical Symptoms

Dep

ress

ion

Lik

elih

oo

d /

Per

cen

tag

e

Series1

28Kroenke K, et al. Arch Fam Med 1994

Medical screening for mood

episodes should include:

- review of systems, physical exam, blood count and chemistries, thyroid function tests, and tests for auto-immune factors. Other studies ( EKG, neuroimaging) should be obtained only if indicated by specific symptoms, not just abnormal mood.

Grief

Medical causes

Other psychiatric disorders

Differential diagnosis of Depression

• Grief is the physical, emotional, somatic, cognitive and spiritual response to actual or threatened loss of a person, thing or place to which we are emotionally attached. We grieve because we are biologically willed to attach. (John Bowlby, Father of Attachment Theory)

What is Grief?

Pharmacotherapy:

• 50 to 70% effective

Selection factors: prior response to agent anticipated side effects concomitant illness potential for drug interactions family history of response patient desire cost

DEPRESSION MANAGEMENT

SSRI

• A class of drugs that inhibit the uptake of serotonin so increases synaptic serotonin levels.

• Many SSRI affect other receptors especially at higher doses.

• Several serotonin (5-HT) receptors subtypes.• The different response we notice in some patients

with one antidepressant versus another because they are structurally unrelated and different response related to different morphology of serotonin transport protein.

Middleton et al: BMJ (2005)

SSRI

• Fluoxetine : 1988• Sertraline : 1992• Paroxetine : 1993• Fluvoxamine : 1994• Citalopram : 1998• S. Citalopram : 2002

SNRIs

• Desvenlafaxine, duloxetine, venlafaxine

Norepinephrine-serotonin

modulator

NASA

• Mirtazapine

Antidepressants: Guidelines

CANMAT (first-line recommendations)

APA (Level 1= recommended with substantial clinical confidence)

SNRIsDesvenlafaxine, duloxetine, venlafaxine

Desvenlafaxine, duloxetine, venlafaxine

SSRIsCitalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline

Citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline

TCAs N/A

Amitriptyline, doxepin, imipramine, nortriptyline, protriptyline, maprotiline trimipramine

Serotonin modulators

N/A Nefadozone, trazodone

Norepinephrine-serotonin modulator

Mirtazapine Mirtazapine

MAOIs MoclobemideIsocarboxazid, moclobemide, phenelzine, selegiline, tranylcypromine

DNRI Bupropion BupropionAPA = American Psychiatric Association; CANMAT = Canadian Network for Mood and Anxiety Treatments; TCA = tricyclic antidepressant; N/A = not applicable; MAOI = monoamine axidase inhibitor; DNRI = dopamine norepinephrine reuptake inhibitorGelenberg et al., 2010. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. Third Edition. Available at http://www.psych.org/guidelines/mdd2010; Lam RW et al. J Affect Disord. 2009;117(Suppl 1):S26-S43.

Principles of prescribing in

depression

• Discuss with the patient choice of drug and utility/availability of other, non-pharmacological treatments.

• Discuss with the patient likely outcomes, such as gradual relief from depressive symptoms over several weeks.

• Prescribe a dose of antidepressant (after titration, if necessary) that is likely to be effective.

• For a single episode, continue treatment for at least 6-9 months after resolution of symptoms (multiple episodes may require longer).

• Withdraw antidepressants gradually; always inform patients of the risk and nature of discontinuation symptoms.

Summary of NICE guidance: treatment for depression

• Antidepressants are not recommended as a first-line treatment in recent-onset, mild depression; active monitoring, individual guided self-help, CBT and/or exercise are preferred.

• Antidepressants are recommended for the treatment of moderate-to-severe depression and for dysthymia.

• When an antidepressant is prescribed, a selective serotonin reuptake inhibitor (SSRI) is recommended.

• All patients should be informed about the withdrawal (discontinuation) effects of antidepressants.

• For treatment-resistant depression, recommended strategies include augmentation with lithium or an antipsychotic or the addition of a second antidepressant .

• Patients with two prior episodes and functional impairment should be treated for at least 2 years.

• The use of ECT is supported in severe and treatment-resistant depression.

Selective serotonin reuptake inhibitors: summary of suggested treatment

• Use of the lowest possible dose• Monitor closely in early stages for restlessness,

agitation and suicidality. This is particularly important in young people (<30 years).

• Doses should be tapered gradually on stopping.

Key points that patients should know about depression

• A single episode of depression should be treated for at least 6-9 months after remission.

• The risk of recurrence of depressive illness is high and increases with each episode.

• Those who have had multiple episodes may require treatment for many years.

• The chances of staying well are greatly increased by taking antidepressants.

• Antidepressants are: - effective - not addictive - not known to lose their efficacy over time - not known to cause a new long-term side-effects.• Medications needs to be continued at the treatment dose. If side-

effects are intolerable, it may be possible to find a more suitable alternative.

• If patients decide to stop their medication, this must not be done abruptly, as this may lead to unpleasant discontinuation effects and confers a higher risk of relapse. The medication needs to be reduced slowly under the supervision of a doctor.

World Health Organisation (1997)

• 300,000 people die from AIDS

• 850,000 people die from car accidents

• 920,000 people die from malaria

• 970,000 people die from lung cancer

• 820,000 people die from suicide

MORTALITY RATES - SUICIDE

World Health Organisation (1997)

• Of 6,003 cases of suicide, the cause was· organic brain syndrome - 5%· substance abuse - 16%· schizophrenia - 10%· affective disorders - 24%· neurotic and personality disorders - 22%· other mental disorders - 21%· no diagnosis -

2%

POSYCHIATRIC DIAGNOSIS

Assessing Suicide Risk

Re-evaluate risk periodically as treatment proceeds

Numerous false negatives and false positives complicate risk assessment

Factors to Consider in Evaluating Suicide Risk

• Lifetime history of attempts • Psychiatric hospitalization

• Suicidal ideation • Disabling medical illness

• Access to means for suicide • Demographic features

• Hopelessness/self-esteem • Psychosocial stressors

• Anxiety • Absence of psychosocial support

• Impulsivity • History of childhood traumas

• Aggression and violence • Family history of or recent exposure to suicide

• Cognition • Absence of protective factors

• Psychotic symptoms • Alcohol or other substance abuse

• Comorbid psychiatric disorders

SUICIDE: A MULTI-FACTORIAL EVENT

Neurobiology

Severe MedicalIllness

Impulsiveness

Access To Weapons

Hopelessness

Life Stressors

Family History

SuicidalBehavior

Personality Disorder/Traits

Psychiatric IllnessCo-morbidity

Psychodynamics/Psychological Vulnerability

Substance Use/Abuse

Suicide

Suicide (risk) Assessment refers to the establishment of a clinical judgment of risk in the very near future, based on the weighing of a very large mass of available clinical detail. Risk assessment carried out in a systematic, disciplined way is more than a guess or intuition – it is a reasoned, inductive process, and a necessary exercise in estimating probability over short periods

COMPONENTS OF SUICIDE

ASSESSMENT

• Appreciate the complexity of suicide / multiple contributing factors

• Conduct a thorough psychiatric examination, identifying risk factors and protective factors and distinguishing risk factors which can be modified from those which cannot

• Ask directly about suicide; The Specific Suicide Inquiry

• Determine level of suicide risk: low, moderate, high• Determine treatment setting and plan• Document assessments

CHARACTERISTICS OF A SUICIDE PLAN

Risk / Rescue Issues:

Method

Time

Place

Available means

Arranging sequence of events

Jacobs (1998)

SUICIDE RISKS IN SPECIFIC DISORDERS

Prior suicide attempt 38.4 0.549 27.5Eating disorders 23.1Bipolar disorder 21.7 0.310 15.5Major depression 20.4 0.292 14.6Mixed drug abuse 19.2 0.275 14.7Dysthymia 12.1 0.173 8.6Obsessive-compulsive 11.5 0.143 8.2Panic disorder 10.0 0.160 7.2Schizophrenia 8.45 0.121 6.0Personality disorders 7.08 0.101 5.1Alcohol abuse 5.86 0.084 4.2Cancer 1.80 0.026 1.3

General population 1.00 0.014 0.72

Condition RR %/y %-Lifetime

Adapted from A.P.A. Guidelines, part A, p. 16

At first psychiatric assessment or admission. With occurrence of any suicidal behavior or

ideation. Whenever there is any noteworthy clinical change. For inpatients:

• Before increasing privileges/giving passes• Before discharge

The issue of firearms:• If present - document instructions• If absent - document as pertinent negative

WHEN TO DOCUMENT SUICIDE RISK ASSESSMENTS

SUICIDE ASSESSMENTCompetency

Document:• The risk level• The basis for the risk level• The treatment plan for reducing the risk

Example: This 62 y.o., recently separated man with recent

stroke is experiencing his first episode of major depressive disorder. He is denying having death wishes or current suicidal ideation. He had serious suicide attempt 5 years ago and he has continued anxiety and hopelessness.

Summary of DSM 5Classification of Bipolar Disorders

* Symptoms do not meet criteria for manic and depressive episodes.

Bipolar features that do not meet criteria for any specific bipolar disorders

At least 2 years of numerous periods of hypomanic and depressive symptoms*

One or more major depressive episodes accompanied by at least one hypomanic episode

FEMALE>MALE

One or more manic or mixed episodes, usually accompanied by major depressive episodes

MALE=FEMALE

Bipolar DisorderNot Otherwise

SpecifiedCyclothymicBipolar IIBipolar I

First, ed. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text Rev. Washington, DC: American Psychiatric Association; 2000:345-428.

Classical mania: the clinical picture

• Euphoria, elation and expansive mood• Overactive, disinhibited, distractible, impulsive

and irritable – and often aggressive• Trail of havoc with overspending and

recklessness• Pressure of speech and flight of ideas• Delusions of grandeur, power, ability and plans• Psychotic symptoms (mood congruent)• Hallucinations

Bipolar disorder: the conventional

view

Stable mood (euthymia)

Mania

Depressive phase

Mania

Maintenance

Bipolar disorder: recurrent illness and

few periods of stability

Subsyndromal mania (hypomania)

Mania

Depressive state

Maintenance phase:note lack of stabilityMinor depressive state

Switch into mania

Mania

Bipolar disorder: a challenge to the conventional view?

Depression Mania

Depression

Polar opposites

Mixed states are commonPrevalence of suicide in maniaSwitching between mania / depression may occur without transition through a normal mood state

Treatment of Bipolar Disorder training astra 2008

Classical mania: the clinical

picture

• Euphoria, elation and expansive mood• Overactive, disinhibited, distractible, impulsive

and irritable – and often aggressive• Trail of havoc with overspending and

recklessness• Pressure of speech and flight of ideas• Delusions of grandeur, power, ability and plans• Psychotic symptoms (mood congruent)• Hallucinations

Bipolar Disorder

• Common illness affecting 2% of the world population (5% if one includes spectrum disorders)

• 6th leading cause of medical disability in the developed nations

• Prominent cognitive abnormalities

1Cookson J. Br J Psychiatry. 2001;178(suppl. 41): s148–s156.2Strakowski SM, et al. Expert Opin. Pharmacother. 2003;4:751-760.

THE LEADING CAUSES OF DISABILITY WORLDWIDE

Impact of Bipolar Disorder Vs. Unipolar Disorder — Heavy Impact

on Daily Life

48

2629

23

5

54

05

1015

2025

3035

4045

50

Ever Fired or Laid Off Supervisor UnhappyWith Work, Behavior, or

Attitude

Jailed, Arrested, orConvicted of a Crime

Other Than DrunkDriving

MDQ positive

MDQ negative

Per

cen

t

* P<0.0001

Calabrese. J Clin Psychiatry. 2003;64:425-432.

Economic Impact and Disability from Bipolar Disorder

• Consistently among 10 leading causes of medical disability in the world

• Total Annual Cost (in the USA): $ 80 Billion o Lost Productivity: $ 50 Billiono Direct treatment costs: $ 10 Billion

Murray, Lopez, 1994; Updated 2004

Bipolar Disorder

• Particularly recalcitrant mental health problem

• Symptomatic at least half the time

• Can have impaired social function even when symptom-free

1Cookson J. Br J Psychiatry. 2001;178(suppl. 41): s148–s156.2Strakowski SM, et al. Expert Opin. Pharmacother. 2003;4:751-760.

BIPOLAR DISORDER

The Major Challenge: Misdiagnosis

· Most frequent misdiagnosis: Unipolar depression

· Treatment as unipolar depression can lead to worsening of symptoms by switching into mania or cycle acceleration

Goodwin & Jamison (1990); Hirschfeld et al (2003); Lish et al (1994)

Bipolar Depression

• 80% of patients exhibit significant suicidality• 60% of patients with dysphoric mania exhibit

suicidality

• Depressive episodes dominate course of bipolar disorder (twice the amount of time as in mania)

• 25-30% of patients initially diagnosed with unipolar depression subsequently have a manic or hypomanic episode

Goodwin FK and Jamison KR. Manic Depressive Illnessn

Bipolar Disorder

• > 50% alcohol and/or other substance abuse

• About 50% attempt suicide

o About 15% succeed

1Cookson J. Br J Psychiatry. 2001;178(suppl. 41): s148–s156.2Strakowski SM, et al. Expert Opin. Pharmacother. 2003;4:751-760.

Treatment Challenges in Bipolar Disorder

• Often unrecognized• Often untreated • Often misdiagnosed• Often inadequately treated• Exacerbated by incorrect treatment

Akiskal. J Clin Psychopharmacol. 1996;16(suppl 1):4S-14S.

The Evolution of Therapies for Bipolar Disorder

Antipsychotics

Seroquel improves mania as early as Day 4 monotherapy YMRS

Seroquel reduces mania within

the first week - Adjunct therapy YMRS

Bipolar Depression

• 50% of first bipolar episodes are depressive episodes

• Depressive episodes in bipolar disorder are associated with considerable morbidity and mortality

• Bipolar depressive episodes have a chronic course

Goodwin FK and Jamison KR. Manic Depressive Illnessn

Olanzapine or olanzapine plus fluoxetine

vs placebo in acute bipolar depression

Quetiapine monotherapy: significant reduction

of depressive symptoms from Week 1

Seroquel improves overall functioning

change in GAS scoreMonotherapy / adjunct therapy

Bipolar Disorder: Summary of Efficacy Evidence from RCTs

Patients’ reasons for taking

medication