Major depressive disorder

By: YOHANES AYELE, M.Pharm,

Lecturer,
Harar Health Science College
yohanesayele@ymail.com

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 Case#2
Ms PS is a 17-year-old woman who presented to her
primary care doctor with a 2-month history of difficulty
in getting to sleep. She described herself as feeling
generally unhappy. She had lost interest in socialising
but was able to perform most of her usual daily
routines. She sometimes felt as though she had little
energy and was spending more time just watching the
television.

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Questions

1. We all feel depressed at one time or another. Does

that mean we have depression? How do we define
clinical depression?
2. Discuss both pharmacological and non
pharmacological management for depression
3. Discuss criteria for selection of antidepressants
4. Discuss issues that need to be addressed during
initiation of antidepressants

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 Definition

• Affective disorder characterized by one or more

major depressive episodes without history of manic,
mixed, or hypomanic episodes.

• It is chronic, recurring and potentially life threatening

illness

• Depression is associated with significant functional

disability, morbidity, and mortality.

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 Epidemiology

• 16.2% of the population had a history of MDD in

their lifetime, and …..
• More than 6.6% had an episode within the past 12
months…….US data
• According to the World Health
Organization…Depression is the leading cause of
disability

• About 33% of all depressed patients attempt…

suicide - about half of them succeed

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 Epidemiology…

• Most patients with MDD are women.

– Prior to adolescence, boys and girls are equally
likely to experience depression.
– In adults, about 2/3 of patients with depression
are female.
• Most patients experience 5–6 episodes during their
lifetimes.

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 Risk Factors
• Genetic predisposition
– 1.5 - 3 x greater: 1st degree relative
– twins: 65% increases incidence
• Age…………elderly higher incidence

• Race…Whites > African Americans

• Co morbidity
• Marital status……….Single>Divorced>Widow
• Substance abuse
• Family history

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 Prevalence of Depression in Specific
Medically ill Population
45
40
35
30
25
20
15
10
5
0
DM MI CRF EPILEPSY STROKE CANCER CHRONIC
PAIN

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 Pathophysiology
Monoamine hypothesis
• Decreased synaptic concentrations of NE and/or
serotonin caused depression.
• However, AD(antidepressants)…. Reuptake blockade
of NTs occurs immediately on administration of an
antidepressant, BUT…the clinical antidepressant
effects are delayed by wks.
• Desensitization or downregulation of NE or 5-HT1A
receptors relate to onset of antidepressant
effects……lead us to recent hypothesis….

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 Pathophysiology…
Dysregulation hypothesis
• Failure of homeostatic regulation of NT systems, rather
than absolute decreases in their activities cause
depression.

• 5-HT, NE, dopamine systems involved in antidepressant

response……………….

• Increased dopamine neurotransmission in mesolimbic

pathway related to antidepressants effect.

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 Clinical Presentation

Emotional symptoms:
– Diminished ability to experience pleasure
– Loss of interest in usual activities
– Sadness
– Pessimistic outlook
– Crying spells
– Hopelessness
– Anxiety
– Feelings of guilt
– Psychotic features (e.g., auditory hallucinations and
delusions)

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 Clinical Presentation…

Physical symptoms:
– Fatigue
– Headache
– Pain
– Sleep disturbance
– Increased/decreased appetite
– Loss of sexual interest
– Gastrointestinal (GI) and cardiovascular
complaints (especially palpitations)

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 Clinical Presentation…

• Cognitive symptoms:
– Decreased ability to concentrate
– Slowed thinking
– Poor memory for recent events
– Confusion
– Indecisiveness
• Psychomotor disturbances may include psychomotor
retardation (slowed physical movements, thought
processes, and speech)
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Diagnostic Criteria

4 Criteria
1. Clinical Symptoms
2. Duration of illness
3. Impact of quality of life
4. Absence of other organic
diseases

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 Diagnostic Criteria
I. Five or more of the following symptoms for at least two-
week period. One of the symptoms is either:
– Depressed mood
– Loss of interest in pleasurable activities

II. The symptoms cause clinically significant distress or

impairment in social, occupational, or other important
areas of functioning.

III. Cannot be established that an organic factor initiated

or maintained the disturbance

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TREATMENT

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 Desired Outcomes
• Eliminate or reduce acute symptoms.
• Facilitate return to premorbid level of functioning.
• Prevent further depressive episodes
• Minimize adverse drug effects.
• Ensure adherence with therapeutic regimen.

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 Treatment principle

Three phases
• Acute treatment phase lasts 6–10 weeks; goal is
remission (i.e., absence of symptoms).

• Continuation phase lasts 4–9 months after remission;

goal is to eliminate residual symptoms and prevent
relapse.

• Maintenance phase lasts at least 12–36 months; goal

is to prevent recurrence of depression.

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 Treatment principle cont…

Continuation phase
• The continuation phase of treatment, generally
lasting six to nine months
• Residual symptoms (partial remission) are strong
predictors of recurrence, early relapse, or a more
chronic future course.
• More than 6 months and psychotic depression
require a longer continuation phase, up to 12
months

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 Treatment principle cont…

Maintenance phase
• Maintenance treatment for 12 to 36 months reduces
the risk of recurrence by two thirds.
• This approach is indicated for patients with
– episodes that occur yearly
– who have impairment because of mild residual
symptoms,
– who have chronic major depression
– who have extremely severe episodes with a high risk
of suicide

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 Treatment principle cont…

• Multimodal approach that includes

pharmacotherapy and psychotherapy.
• Treatment requires the monitoring of clinical
responses, including suicidal ideation and side effects

• Educate patient and family regarding the delay in

antidepressant effects and importance of adherence.

• Antidepressants are essentially equal in efficacy

when administered in comparable doses.

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 Treatment principle cont…

• About 65–70% of patients improve with drug

therapy.
• Often takes………. 4-6 weeks for response
• Vegetative symptoms(altered sleep or appetite,
decreased energy, excessive worrying and irritability)
………..tend to improve first, cognitive symptoms
(guilt or pessimism, poor concentration,
hopelessness or sadness, and decreased, Libido)take
longer
• Maintain meds for 6-12 months

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 Non-drug Therapies for Depression

• Psychotherapy may be first-line in milder to

moderate episodes….

• But not for patients with severe and/or psychotic

major depressive disorders.

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 Non-drug Therapies for Depression cont…

• ECT is safe and effective and may be considered when;

– rapid response is needed(first week or two of
treatments)
– risks of other treatments outweigh potential benefits
– there has been poor response to drugs
– patient expresses preference for ECT
• Overall response ….70% to 90%
• Relapse rates during the year following ECT high unless
maintenance antidepressants prescribed.

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 Non-drug Therapies for Depression cont…

• Any therapeutic approach to mood disorders should

seek to reverse unhealthy or destructive lifestyle
habits
• Consider other activities that may relieve stress and
facilitate well-being.
• Alcohol, recreational drug use, and excessive
caffeine consumption should be minimize
• Sleep habits should be evaluated and improved to
ensure optimal rest

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 Pharmacological options

Different categories:
1. SSRIs
2. TCAs
3. Serotonin norepinephrine reuptake inhibitors (SNRIs)
4. Monoamine oxidase inhibitors (MAOIs)
5. Miscellaneous (e.g., trazodone, mirtazapine)

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SSRIs

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 SSRIs

• 1st line drugs….Due to their relative safety &

acceptability
• Produce little or no sedation
• Not produce anticholinergic side effects
• Devoid of α AR blocking action (no postural
hypotension)- suitable for elderly patients
• No seizure precipitating propensity
• No weight gain
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Tricyclic Antidepressants (TCAs)

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 Major limitations of conventional TCAs

• Anticholinegics, cardiovascular & neurological side

effects
• Relatively low safety margin, dangerous in over
dose
• Lag time 2-4 weeks before antidepressant action
manifests
• Incomplete response by significant number of
patients & some do not respond

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 Antidepressant Side effects
SSRI’s
• Nausea…. transient effect that diminishes after the
first week of treatment

• Local GI irritation 1 to 2 hours after oral

administration…. take the medication after a meal or
snack, particularly during the first week of therapy

• Diarrhea ….Sertraline, fluoxetine, and citalopram

• Constipation …paroxetine

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 Antidepressant Side effects…

• Central nervous system:

– Nervousness, insomnia………fluoxetine
– Somnolence, tremor, dry mouth ………..paroxetine
• Sexual dysfunction ……All
• Acute side effects decreases over time !!!!
• Late onset side effects include… wt gain (up to 10 Ib),
fatigue, apathy(lack of enthusiasm)

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 Antidepressant Side effects…

SSRI – Serotonin Syndrome

• A "serotonin syndrome" may occur, where mental status
changes along with ………
– Agitation sweating
– Shivering tremors
– Diarrhea uncoordination
• This syndrome may be life-threatening.
• SSRIs should not be used with any drug that
increases serotonin concentrations, including….
– Tramadol, Meperidine, SNRI

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 Selection of a First-Line Antidepressant
Medication
Patient history
• Age group
• Children and adolescents… SSRI (fluoxetine)
• Adults <65 yr… SSRI or SNRI
• Family history of response… Same medication that
was effective in first-degree relative
• Past response …Same medication that was effective
previously

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 Selection of a First-Line….

Depression characteristic
• Bipolar depression… Mood stabilizer (lithium or
lamotrigine) plus antidepressant
• Psychotic depression… Antidepressant plus
antipsychotic (atypical)
• Depression with features of obsessive–compulsive
disorder…SSRI
• Panic attacks… SSRI

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 Monitoring

• Initial response….. 2-4 wks

• If there is a response but not adequate response after 3-
4 wks …………….dose.
• If no response at all, switch first in the same
class…then….if no response to other class

• Best predictors of outcome are improvements in

anhedonia (loss of pleasure), psychomotor retardation,
and loss of interest.
• Suicidal ideation, pessimism, guilt, and other changes in
cognition may take longer to improve

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 Monitoring…

• Evaluate patients for emergence of suicidal ideation

after starting any antidepressant, especially in first
few weeks of treatment.

• If successful, continue medications for 6–12 months

before tapering is considered.

• When discontinuing medications, taper gradually

over several months.

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 Special patient populations

• Depression in bipolar disorder carries the risk of a

switch into mania

• Mood stabilizers with antidepressant properties,

such as lithium and lamotrigen

• For severe bipolar depression, a combination of an

antidepressant and a mood stabilizer should be
considered from the outset

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 Children and adolescents
• Recommend psychotherapy for children with
depression.
– Save antidepressants for those who don't benefit from
counseling.
• Advise parents with children on antidepressants to
report any increase in agitation or suicidal thoughts
or behaviors.
• Fluoxetine is the only antidepressant with
demonstrated efficacy in childhood and adolescent
depression and approved for pediatric use.

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 Pregnant women

• During pregnancy, nondrug approaches preferred (if

effective), but pregnant women who discontinue
antidepressants may be more likely to relapse during
pregnancy than those who continue treatment.

• No major teratogenic effects identified with SSRIs or

TCAs, but fluoxetine may be associated with low
birth weight and respiratory distress.

• Paroxetine ….. category D

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 Challenges to treatment

• Major challenge is many patients receive inadequate

treatment

• Patients change treatment too quickly

• Patients do not adhere to long-term treatment

and/or discontinue treatment before an effect is
observed(>40% stops inside 3 mo)

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 Treatment Resistant Depression
• Approximately 29% to 46% of patients with
depression do not have good response to
antidepressants.
• Intolerance is frequently a cause of treatment failure
or inadequate response.

• Antidepressant treatment at an adequate dose for at

least four to eight weeks is necessary

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 Treatment Resistant Depression…
• Higher doses may be an option, but this risks more
frequent and severe adverse effects.

• Another approach is augmentation therapies….with

the following therapies (lithium, tyroid,
bupropione,etc), phototherapy, psychotherapy

• Yet another approach is to ….switch the drug

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 Switching Antidepressants

Direct switch
– Some patients can switch directly from one SSRI to
another SSRI,
– Exception…..patients switching from Prozac should
wait 4 to 7 days because of its long half-life...then
start a low dose of another SSRI.
Cross-tapering
– Gradually reducing the dose of the old drug...while
simultaneously increasing the dose of the new one
works well.
– Recommended this when switching to meds with a
different mechanism

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 Antidepressants and ….Increased Suicidal Risk

• The risk of committing suicide is found to be more in the

patients undergoing antidepressant treatment.

• If the person is taking the antidepressants for the first

time or if the dose has changed abruptly, then monitoring
of the person is essential as they might commit suicide.

• Antidepressants will not provide benefits to all the

depression patients

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 Check point
1. In a patient beginning maintenance therapy with an
antidepressant, what is the minimum recommended duration of
treatment?
A. 4 months
B. 9 months
C. 12 months
D. 36 months
2. In a patient experiencing a major depressive episode, what
should be considered prior to labeling him or her a
nonresponder to medication?
A. Adequate dose for adequate duration
B. Adherence to prescribed regimen
C. Proper monitoring of response
D. All the above

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 Check point..
3. Which of the following antidepressants would be the least
likely to cause a withdrawal syndrome based on its
pharmacokinetic profile?
A. Fluoxetine
B. Duloxetine
C. Paroxetine
D. Sertraline
4. A patient with MDD was started with Zoloft® 100 mg qd. For 6
weeks with no change in his symptoms. Your recommendation is:
A. switch to another SSRI (Prozac®)
B. Increase the dose of Zoloft®
C. wait for another week

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THANK YOU !!!

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