Depressive Illness

Asad Tamizuddin Nizami

Assistant ProfessorInstitute of PsychiatryRawalpindi Medical College

Major Depressive Episode

A marked change from previous functioning for at least two weeks with 5 or more of the following symptoms:

▫ Depressed Mood (Irritability/anger in adolescents)

▫ Markedly diminished interest or pleasure▫ Significant change in appetite and/or weight▫ Insomnia or hypersomnia▫ Psychomotor agitation or retardation▫ Fatigue or loss of energy▫ Feelings of worthlessness or excessive guilt▫ Diminished concentration ▫ Recurrent thoughts of death

Epidemiology• Depression is the fourth most important contributor to the

global burden of disease

• The point prevalence for depression is 1.9% for males and 3.2% for females.

• 5.8% of males and 9.5% of females will develop a depressive episode within a 12-month period.

• Every year 5-8% of the adult population gets a depression .

• Lifetime risk for a severe depression amounts to 12-16%.

Marianne C. Kastrup, Armando Báez Ramos . Global mental health- secondary publication Danish Medical Bulletin - No. 1. February 2007. Vol. 54 Pages 42-3

In Pakistan………….

M en1 0 % (M u m ford 2 0 0 0 )- 3 3 % (Javed 1 9 9 4 )

W om en2 8 .8 % (R ab b an i)- 6 6 % (M u m ford 1 9 9 7 )

R an d om C om m u n ity S am p le3 3 .6 2 %

Percentage of major diagnostic categories during four years in IOPjournal of CPSP (2001)

Fig.3 Percentage of major diagnostic categories.

overall%

Males

Females

overall% 8.40% 37% 11.40% 4.80% 10.60% 1.50% 1.43% 4.80%

Males 5.70% 18% 4.15% 2.90% 10.60% 0.92% 0.95% 0.60%

Females 2.70% 19% 7.20% 1.90% 0% 0.66% 1.90% 4.20%

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Etiology of Depression - Genetics

• Indirect evidence suggests that the glycogen synthase kinase-3beta (GSK3beta) gene might be implicated in major depressive disorder (MDD). A recent study identified a link between the GSK3 beta polymorphism and the structural brain changes in major depressive disorder.(2)

• A meta-analysis yielded little evidence that the serotonin transporter genotype alone or in interaction with stressful life events was associated with an elevated risk of depression in men alone, women alone, or in both sexes combined.(3)

•

• 2. Inkster B et al. Association of GSK3Beta polymorphism with structural brain changes in major depressive disorder. Arch Gen Psychiatry. 2009 Jul;66(7):721-8.

3. Risch N et al. JAMA. 2009 Jun 17;301(23):2462-71. Interaction between the serotonin transporter gene (5-

HTTLPR), stressful life events, and risk of depression: a meta-analysis.

Neurobiology

• In recent years the monoamine theory of depression has

given way to a molecular and cellular theory that suggests that antidepressants work by increase in brain levels of neurotrophic factors such as brain-derived neurotrophic factor (BDNF).

• Basic laboratory work has documented the importance of neurotrophins in neuronal survival and synaptic plasticity.which lead to structural brain changes i.e hippocampal atrophy seen in depression(1)

Dan J. Stein, Brain-Derived Neurotrophic Factor: The Neurotrophin Hypothesis of Psychopathology

Neurobiology

• BNDF plays a role in a range of neurodegenerative, neuroinflammatory, and neurodevelopmental disorders, as well as in some psychiatric and substance use disorders.

• Decreased hippocampal BDNF mRNA and cell atrophy are, for example, seen in several animal models of depression.

• Depression is associated with decreased hippocampal volume, and depressed patients have decreased hippocampal BDNF.

• Chronic stress leads to hippocampal cell loss and to down-regulation of BDNF

Dan J. Stein, Brain-Derived Neurotrophic Factor: The Neurotrophin Hypothesis of Psychopathology

Interestingly…………..

• In general practice 1 in 5 new consultations are for pain symptoms for which no specific cause is found.

• The pain symptoms of 1/3 of all patients seen in medical clinics remain medically unexplained at the time of discharge.

• Research has indicated• 34% of patients with joint or limb pain, • 38% of patients with back pain, • 40% of patients with headache, • 46% of patients with chest pain, and • 43% of patients with abdominal pain

had Depression.

Kroenke K, Spitzer RL, Williams JB, et al. Arch Fam Med. 1994;3:774-779.

1. Simon GE, et al. N Engl J Med. 1999;341(18):1329-1335.

In primary care, physical symptoms are often the chief complaint in depressed patients

N = 1146 Primary care patients with major depression

In one study 69% of diagnosed depressed patients reported unexplained physical symptoms as their chief compliant1

Is there a connection between pain & depression……..

• There is a Neurochemical overlapping in the phenomena of pain complaints and depression.

• Serotonin (or 5-HT) and norepinephrine have emerged as 2 neurotransmitters that are involved in both pain and depression.

Sex

Appetite

Aggression

Concentration

Interest

Motivation

Depressed Mood

Anxiety

Irritability

Thought process

References:

1. Adapted from: Stahl SM. In: Essential Psychopharmacology: Neuroscientific Basis and Practical Applications: 2nd ed. Cambridge University Press 2000.

2. Blier P, et al. J Psychiatry Neurosci. 2001;26(1):37-43.

3. Doraiswamy PM. J Clin Psychiatry. 2001;62(suppl 12):30-35.

4. Verma S, et al. Int Rev Psychiatry. 2000;12:103-114.

Norepinephrine (NE)Serotonin (5-HT)

Vague Aches and pain

Both serotonin and nor epinephrine mediate a broad spectrum of depressive symptoms

Serotonin5HT and Nor epinephrineNE in the brain

Limbic System

Locus Ceruleus (NE Source)

Prefrontal Cortex

Raphe Nuclei (5-HT source)

Cooper JR, Bloom FE. The Biochemical Basis of Neuropharmacology. 1996.

Adapted from References:

1. Stahl SM. J. Clin Psych. 2002;63:203-220.

2. Verma S, et al. Int Rev Psychiatry. 2000;12:103-114.

3. Blier P, et al. J Psychiatry Neurosci. 2001;26(1):37-43.

•Dysregulation of Serotonin (5HT) and Norepinephrine (NE) in the brain are strongly associated with depression

•Dysregulation of 5HT and NE in the spinal cord may explain an increased pain perception among depressed patients1-3

•Imbalances of 5HT and NE may explain the presence of both emotional and physical symptoms of depression.

Descending Pathway

Ascending Pathway

AscendingPathway

DescendingPathway

Research suggests that unexplained pain can be the best indicator of depression,

especially among the elderly.

Stewart RB, Blashfield R, Hale WE, et al. J Fam Pract. 1991;32:497-502.

Ongoing untreated somatic depression lead to structural changes in the central nervous system and augments the risk of

persistent pain’’

Areas of the brain which are involved in memory and decision making undergo structural changes due to stress, which cause long term imbalances in hormonal

regulation”

• Hippocampus• Prefrontal cortex • Amygdala

Undergo changes in size and function in depression

• Dentate gyrus continues to produce new neurons in adult life

• this is suppressed by acute and chronic stress and

• restored by

antidepressant treatment

The loss of neurons in hippocampus due to stress is reversible if the stress is

terminated at the end of 3 weeks

Stress also suppresses neurogenesis and causes dendritic shrinkage

1 .Kessler et al. Arch Gen Psychiatry, 1995 2. DSM-IV 3. Rasmussen. Psychopharmacol Bull, 1988 4. Van Ameringen et al. J Affect Disord,

1991 5. Brawman-Mintzer, Lydiard RB. J Clin Psychiatry, 1996 6. Stein et al, Am J Psychiatry, 2000

MajorDepression

MajorDepression

Posttraumatic Stress DisorderPosttraumatic Stress Disorder

Social Phobia (Social Anxiety Disorder)

Social Phobia (Social Anxiety Disorder)

OCDOCD

Panic DisorderPanic Disorder

GADGAD

8%-39% ofPatients with GAD5

67% of Patientswith OCD3

34-70% of Patients withSocial Phobia4,6

48% of Patients with PTSD1

50% to 65% of Patientswith Panic Disorder2

Comorbid Mood and Anxiety Disorders Lifetime Comorbidity

Aims Of Treatment

TREATMENTTREATMENT

RESTORE RESTORE ROLE ROLE

FUNCTIOFUNCTIONN

REDUCE SIGNS, SYMPTOMS

MINIMIZE RELAPSE/RECURRE

NCE RISK

Treatment Options

• Antidepressants

• Combination Therapies

• Psychotherapy

• ECT

STEPS: Antidepressant Selection• Safety

Drug-drug interaction potential• Tolerability

Acute and long term• Efficacy

Onset of actionTreatment and prophylaxis

• Payment Cost-effectiveness

• SimplicityDosingNeed for monitoring

Antidepressants Groups

• TCAs : Amitriptyline, Doxepine, Trimipramine, Clomipramine and other.

• SSRI : Fluvoxamine, Fluoxetine, Paroxetine, Sertraline, Citalopram, Escitalopram

• RIMA :(Reversible inhibitor of MAO type A) Moclobemide

• SNRI : (Reuptake inhibition of NA/5-HT ) Venlafaxine

Antidepressants Groups

• NaSSA : (5-HT2 and 5-HT3 antagonist,H1 antagonist.)

Mirtazapine

• DSA : (5-HT2 antagonist and 5-HT reuptake inhibitor)

Nefazodone

• NARI (SNRI) : (Selective NA reuptake inhibitor) Reboxetine

Adverse events—a significant cause of treatment discontinuation

Poor tolerability in early therapy

Drop out of SSRI therapy

Lin EHB et al. Medical Care 1995; 33:67–74.Maddox JC et al. J Psychopharmacol 1994; 8:48–53.

Early drop out – other evidence

• Early drop out is common among patients taking antidepressants:

▫28% by week 4*▫43% by week 8*▫52% by week 12*

* Maddox JC et al. J Psychopharmacol 1994; 8:48-53

N = 672; SSRIs included paroxetine or fluoxetineBull SA, et al. Ann Pharmacother. 2002;36:578–584.

Most common early adverse events resulting in dropouts (> 5%)

Nausea Headache

Anxiety Drowsiness

Adverse Events Are A Major Cause of Early Dropout with SSRI Treatment

1 Lin EHB et al. Medical Care 1995; 33:67–74. 2 Maddox JC et al. J Psychopharmacol 1994; 8:48–53. 3 Golden RN et al. J Clin Psychiatry 2002; 63:577-584

Nausea is one of the most common side effects

• SSRIs have been associated with early GI adverse events, resulting in:▫ poor compliance▫ compromised long-term efficacy▫ premature termination of treatment1,2

• Nausea is a leading cause of premature treatment discontinuation for the SSRIs and serotonin norepinephrine reuptake inhibitors3

• Clinical trials in major depression with paroxetine IR (n = 6145)▫ most common event associated with withdrawal on paroxetine

IR was nausea (3.2% vs. 1.1% on placebo).

• Paroxetine CR was developed to minimise early-onset nausea through a shifting of the drug absorption site (lower in GI tract)

Summary

•Patients have a high rate of non-adherence with SSRIs due to adverse events

•First few weeks of therapy are critical•Monitor medication compliance during

this time period•Choose a medication that is effective and

generally well tolerated across multiple indications

Role of Psychotherapy?• Psychotherapy either alone or in combination

with medication, has been shown to be effective in the treatment of comorbid pain and depression

• Some studies have found that the combination of medical and psychotherapeutic treatments provides better results than medication alone.

Murphy GE, Simons AD, Wetzel RD, Lustman PJ. Arch Gen Psychiatry. 1984;41:33-41.

Thank you