HH Case

HH is a 26 year old female who presents accompanied with her husband with a c/c of a depressed mood and not wanting to live anymore because she feels as her life has no purpose. Her husband explains that this has been for the past 2 months.

HH Case

Upon further questioning, you find out she “doesn’t feel like she has energy” even though she sleeps for most of the day, and she has lost about 6 kg due to her loss of interest in eating. Her husband says that she doesn’t like to go out to her favorite restaurants nor does she enjoy shopping as she used to in the past.

Epidemiology

• Annual incidence of major depression is estimated to be 6.6%

• Life time incidence of depression in KSA 17%• The lifetime prevalence rate is 17%

– One in four females (10–24%) is affected– One in eight males (5–12%) is affected

• Major depression is most common between the ages of 25 and 44

What is a Major Depressive Episode?

• Must last at least 2 weeks• At least 5 of the criteria with one including

depressed mood or decreased interests• Must cause clinically significant impairment

What is a Major Depressive Episode?

• Depressed mood and SIG-E-CAPS criteria– S: Suicidal ideation– I: decreased Interests– G: excessive Guilt (worthlessness, hopelessness)– E: decreased Energy– C: decreased Concentration– A: Appetite changes– P: Psychomotor retardation or agitation– S: Sleep disturbance

HH Case

HH is a 26 year old female who presents accompanied with her husband with a c/c of a depressed mood and not wanting to live anymore because she feels as her life has no purpose. Her husband explains that this has been for the past 2 months.

HH Case

Upon further questioning, you find out she “doesn’t feel like she has energy” even though she sleeps for most of the day, and she has lost about 6 kg due to her loss of interest in eating. Her husband says that she doesn’t like to go out to her favorite restaurants nor does she enjoy shopping as she used to in the past.

HH Case

The Hamilton Rating Scale for Depression (HAM-D) is used to rate HH’s degree of depression. It is determined that she has moderate depression with melancholic features.

Rating scales

• General purpose– Brief Psychiatric Rating Scale (BPRS), investigator-rated– Hopkins Symptom Checklist (SCL-90), patient-rated

• Disease-specific rating scales (depression)– Investigator-rated

• Hamilton Rating Scale for Depression (Ham-D, HRSD)• Montgomery-Asburg Depression Rating Scale (MADRS)

– Patient-rated• Beck Depression Inventory (BDI)• Zung Self Rating Scale

Specific features of diagnosis1) Mild

a) Minimum requirement to make diagnosisb) Minor functional impairment

2) Moderatea) Greater degree of functional impairment

3) Severea) Marked interference with social and/or occupational

functioningb) Suicidal ideation

Journal ofAffectiveDisorders150(2013)384–388http://www.psy-world.com/online_hamd.htm

Depression Sub-classificationA. Melancholic (endogenous)

A. Weight lossB. Early morning

awakeningC. Extreme listlessnessD. Intense guiltE. Inability to cheer up

even for a moment

B. Psychotic (or delusional)A. Mood congruentB. Poverty, physical

illness, moral transgressions

C. Occur in 10–25%

C. Atypical depression (exogenous)

A. Increased appetiteB. Weight gainC. Excessive sleepD. Leaden sensation in

the arms and legsE. Mood reactive

D. Postpartum DepressionA. Onset of depression

within 4 weeksB. Occurs in 10% to 26%

Treatment Goals

Treatment Goals

• Eliminate or significantly reduce symptoms. Remission (symptom-free or nearly symptom-free) should be the goal of treatment of depression, although a majority of patients continue with residual symptoms

• Restore functioning to premorbid levels• Prevent depressive relapse• Minimize medication side effects• Ensure adherence with the prescribed regimen• Incorporate psychotherapy• Improve quality of life

Choices of Treatment

Psychotherapya. Mild to moderate MDDb. Less chronicc. No psychoticd. Past positive responsee. Medical contraindication to medications

Medicationa. Mild to moderate MDDb. Chronicc. Recurrentd. Psychotice. Melancholicf. Past positive responseg. Family historyh. Failure to respond to psychotherapy

Choices of Treatment

Medication and psychotherapya. Moderate to severe MDDb. Chronicc. Partial response to either therapy aloned. Personality disorder

Electroconvulsive therapya. Psychoticb. Severe MDDc. Past positive responsed. Failure of several medications or combined treatment trialse. Need for rapid responsef. Medical contraindications to medications

Antidepressant therapy

• Initiation of therapy1. Initiate therapy with divided doses to minimize

adverse drug reactions2. Consider age of patient and adjust accordingly3. Target dose should be achieved as quickly as

tolerated4. Improvement in 3–4 weeks of therapy5. Maximal response in 8 weeks of therapy

HH Case

You recommend that HH starts on medication and psychotherapy. She calls 2 weeks later and states that she still has somewhat of a depressed mood. She thinks that she needs to switch to a new medication. Upon questioning, she acknowledges that her eating has improved and she is sleeping less.

Acute treatment1. Duration usually 6–12 weeks2. Response (symptom remission)

a) Definitioni) Complete (> 50% reduction)ii) Partial (> 25% but < 50%)iii) No response (< 25%)

b) Rate of responsei) First week

• Decreased anxiety• Improvement in sleep• Improvement in appetite

ii) 2–3 weeks• ↑ Activity, libido, self-care, memory• Thinking and movements normalize• Sleeping and eating patterns normalize

iii) 4-6 weeks– Improved mood– Decreased suicidal ideation– Increased libido

HH Case

HH returns to the clinic after 2 months (~8 weeks). She states that she is much better than before. Upon assessment and completion another HAM-D rating scale and determine that she is in remission. She asks if she should discontinue her medication now.

Continuation treatment

1. To prevent relapse2. Continue antidepressant 4–9 months after

acute phase at same dose3. Continue with the same treatment and the

same dose in acute phase

Maintenance treatment

1. Variable time duration (1-3 years; indefinitely for some patients)2. Use full therapeutic doses3. Goal is to prevent new episode (recurrence/relapse)

Prophylaxis• Chronic antidepressant therapy may be necessary for certain patients experiencing

the following:Potential candidates

a) Three or more episodes of MDD or have chronic MDDb) Patients with additional risk factors for recurrence (presence of residual

symptoms, ongoing psychosocial stressors, early age at onset, and family history of mood disorders)

c) Considerations: patient preferences, the type of treatment received, the presence of side effects during continuation therapy, the probability of recurrence, the frequency and severity of prior depressive episodes (i.e. psychosis or suicide risk), the persistence of depressive symptoms after recovery, and the presence of co-occurring disorders

Factors to be consider on Selection of an antidepressant

• Neurotransmitter profile family history• Side effect profile potential drug interactions• Patient age• Cost• Ease of administration (compliance)• Safety profile • Patient preference• Patient experience with antidepressants, suicide

risk

ANTIDEPRESSANT MEDICATION: REVIEW

TreatmentF:\WFGSG_DEPRESSION.pdf

Psychotherapy

Medication

Tricyclic Antidepressants TCA

Monoamine Oxidase Inhibitors MAOI

Selective serotonin reuptake inhibitors

(SSRIs)

Dual Reuptake Inhibitors

Drugs with Novel Mechanism

Benzodiazepine (Adjunctive Therapy )

Electro-convulsive

Therapy ECT

ANTIDEPRESSANT MEDICATIONS

• The U.S. Food and Drug Administration (FDA) now requires all antidepressant drugs to include boxed warnings about increased risk of suicidal ideation and behavior in children and adolescents and in young adults (up to age 24)

• All antidepressants are potentially effective in the treatment of depression, they show similar efficacy when used in adequate dosages

Antidepressants

1. TCA = Tricyclic Antidepressants 2. MAOI = Monoamine Oxidase Inhibitors3. SSRI = Selective Serotonin Reuptake Inhibitor

4. SNRI = Serotonin-Norepinephrine Reuptake

Inhibitor

Pathophysiology hypothesesBiogenic amine

• Central nervous system (CNS) deficiency in dopamine, norepinephrine, and/or serotonin• Based on knowledge that antidepressants increase monoamine neurotransmission

Permissive• An underlying deficiency of serotonin accompanied by decreased noradrenergic

transmission

Neuroendocrine finding

• It has been suggested that the inability of brain to suppress the HPA (hypothalamic–pituitary–adrenal) axis and the associated stress response could lead to depression

• Serotonin exerts a strong influence on HPA axis

ANTIDEPRESSANT MEDICATION

ANTIDEPRESSANT MEDICATIONS

Tricyclics “TCAs”Amitriptyline 50 –300 mg/dayClomipramine 25 –250 mg/dayDoxepin 75 divided doses –300 mg/dayTrimipramine 50 –300 mg/day Imipramine 50 –300 mg/dayDesipramine 50 –300 mg/dayNortriptyline 25 –200 mg/dayProtriptyline 10 – 60 mg/day

Tertiary amines

Secondary amines

ANTIDEPRESSANT MEDICATIONS

Tricyclics• Block the reuptake of both norepinephrine (NE) , serotonin (5HT),

muscarinic, alpha1 adrenergic, and histaminic receptors. The extent of these effects vary with each agent resulting in differing side effect profiles

• TCA have effects on cardiac action potentials typical of class IA antiarrhythmics

• The TCAs can be lethal in overdose, caused by cardiovascular effects including severe hypotension, seizures, and cardiac arrhythmias. Treatment of overdose should be focused on controlling seizures and correcting arrhythmias

Possible Adverse Effects of Reuptake Blocking of Antidepressant Drugs*

Nausea, Diarrhea and Gastrointestinal disturbances (including weight loss early in treatment, weight gain late in treatment)

Nervousness, Insomnia, Fine tremors Increase or decrease in anxiety (dose dependent) Sexual dysfunction (including decreased libido) Extrapyramidal adverse effects

Serotonin Reuptake Blocking

Possible Adverse Effects of Reuptake Blocking of Antidepressant Drugs*

Blurred vision, Dry mouth, Constipation, Urinary retention (Act synergistically with anticholinergics)

Tremors, Increased arousal and Insomnia Tachycardia Raised blood pressure Blockade of antihypertensive effects

NorepinephrineReuptake Blocking

Possible Adverse Effects of Receptor Blocking of Antidepressant Drugs*

Dry mouth, Constipation, Urinary retention Sinus tachycardia Blurred visionAttack or exacerbation of narrow-angle glaucomaCognitive impairmentMemory dysfunction

BlockingMuscarinicReceptors

Night-time sedationImpairment of psychomotor coordination during the Daytime drowsinessWeight gainPotentiation of central depressant drugs

BlockingHistamine 1 Receptors

Tricyclic Antidepressants

Neurological effects• TCAs can induce mild myoclonus, this may be a sign of toxicity

• In overdoses, tricyclic antidepressants can precipitate seizures

Tricyclic Antidepressants

Contraindications• Concomitant use of a monoamine oxidase inhibitor (MAOI)

within the past 14 days• During pregnancy or lactation• Patients with narrow-angle glaucoma

Monoamine oxidase inhibitors

Monoamine oxidase irreversible, non selective inhibitors “MAOIs”• Phenelzine 15 –90 mg/day • Tranylcypromine 10 – 60 mg/day• Inhibit the enzymatic breakdown of 5HT, dopamine, and NE• Reserved for atypical or resistant depression due to their

toxicity profile

Monoamine oxidase inhibitors

Reversible monoamine oxidase inhibitors “RIMA”

Moclobemide

There is no need to restrict dietary tyramine

Monoamine oxidase inhibitorsHypertensive crises

• Severe headache, nausea, neck stiffness, palpitations, profuse perspiration, and confusion, possibly leading to stroke and death

Monoamine Oxidase Inhibitors

Cardiovascular effects• Orthostatic hypotension is commonly seen during MAOI

treatment• MAOI use can also be associated with the development of

peripheral edema

Monoamine Oxidase Inhibitors

• On discontinuation of MAOI therapy, enzyme inhibition will continue until the formation of new MAO enzymes (about 2 weeks).

2 weeks5 weeks 2 weeks

COMPARATIVE EFFICACY

TCAs

and

others

SSRI

s

COMPARATIVE SAFETY

SSRIs

TCAs

ANTIDEPRESSANT MEDICATIONS

Selective serotonin reuptake inhibitors “SSRIs”Fluoxetine 20–80mg/daySertraline 25 –100 mg/day Paroxetine 10–40 mg/day Fluvoxamine 50 –300 mg/day Citalopram 20 – 40 mg/dayEscitalopram 10-20 mg/day

Mechanism of SSRIs

Possible Adverse Effects of Reuptake Blocking of Antidepressant Drugs*

Nausea, Diarrhea and Gastrointestinal disturbances (including weight loss early in treatment, weight gain late in treatment)

Nervousness, Insomnia, Fine tremors Increase or decrease in anxiety (dose dependent) Sexual dysfunction (including decreased libido) Extrapyramidal adverse effects

Serotonin Reuptake Blocking

Selective serotonin reuptake inhibitors

Gastrointestinal• SSRIs cause nausea, vomiting, and diarrhea to a greater extent

than tricyclic antidepressant medications• These adverse events are generally dose dependent and tend

to dissipate over the first few weeks of treatment

Selective serotonin reuptake inhibitors

Activation/insomnia

• In some patients, SSRIs may precipitate or exacerbate restlessness, agitation, and sleep disturbances

• These side effects often attenuate with time

• Anxiety may be minimized by introducing the agent at a low dose; insomnia may be effectively treated by the addition of trazodone, up to 100 mg at bedtime

Selective serotonin reuptake inhibitors

Sexual side effects

• Loss of erectile or ejaculatory function in men and loss of libido and anorgasmia in both sexes may be complications SSRIs.

• Lowering the dose, discontinuing the antidepressant, or substituting another antidepressant such as bupropion

• Specific pharmacologic treatments that can be added for arousal or erectile dysfunction include sildenafil, yohimbine

Selective serotonin reuptake inhibitorsSerotonin syndrome. • SSRI used associated with the rare

development of a syndrome due to an excess of serotonergic activity.

• Features of serotonin syndrome include:

(abdominal pain, diarrhea, flushing, sweating, hyperthermia, lethargy, mental status changes, tremor and myoclonus, rhabdomyolysis, renal failure, cardiovascular shock, and possibly death.)

• it is usually associated with the simultaneous use of multiple serotonergic agents such as SSRIs together with MAOIs.

• When patients are being switched from an SSRI with a short half-life to an MAOI, a waiting period of at least 2 weeks is needed between the discontinuation of one medication and the initiation of the other.

• When switching from fluoxetine to an MAOI, a waiting period of at least 5 weeks is needed before the MAOI is started.

ANTIDEPRESSANT MEDICATIONS

Atypical Antidepressants Norepinephrine-serotonin modulator

Mirtazapine 15 – 45 mg/day

Serotonin-norepinephrine reuptake inhibitors Venlafaxine 75 –375 mg/day

Dopamine-norepinephrine reuptake inhibitors

Bupropion 150 – 450 mg/day

MIRTAZAPINE

• The drug mainly affects serotonin (5-HT) receptors of the 5-HT2 and 5-HT-3 subtypes, possessing low affinity for 5-HT1A, 5-HT1B, and 5-HT1C receptors; as a 5-HT2 antagonist

• Mirtazapine has strong alpha-2 receptor blocking actions

MIRTAZIPINE SIDE EFFECTS

• The most common side effects from mirtazapine include sedation, increased appetite, dry mouth, and weight gain.

• Mirtazapine has also been shown to increase serum cholesterol levels in some patients.

• Although agranulocytosis and neutropenia has been observed to occur in patients taking mirtazapine. (Rarely )

VENLAFAXINE

• Venlafaxine is a dual inhibitor of serotonin and norepinephrine at doses generally greater than 150 mg/ day. At doses lower than 150 mg, venlafaxine primarily inhibits serotonin reuptake

• The initial recommended dosage of regular-release venlafaxine is 75 milligrams (mg)/day; the dose may be titrated at 4-day intervals to a maximum dose of 375 mg/day

• Major Side Effect: Hypertension• Venlafaxine is indicated for both generalized anxiety disorder

and major depression. It is not recommended in patients with uncontrolled hypertension or recent MI or cerebrovascular disorders

BUPROPION • Bupropion is a weak inhibitor of dopamine and norepinephrine reuptake,

with an active metabolite that is a norepinephrine reuptake inhibitor. • Side effect including headaches, tremors, and seizures • Bupropion is contraindicated for use in patients with seizure disorders

and eating disorders

DA reuptake

inhibition

Reduce depression Psychomotor activation Antiparkinsonian effects

5HT2

block

Reduce depression Reduce suicidal behavior Antipsychotic effects Hypotension Ejaculatory dysfunction Sedation

NEreuptake

inhibition

Reduce depression Antianxiety effects Tremors Tachycardia Erectile/ejaculatory dysfunction

5HT reuptakeinhibition

Reduce depression Antianxiety effects GI disturbances Sexual dysfunction

Alpha1

block

Postural hypotension Dizziness Reflex tachycardia Memory dysfunction

Anxiety

ACh block

Blurred vision Dry mouth Constipation Sinus tachycardia Urinary retention Cognitive dysfunction

H1

block

Sedation/drowsiness Hypotension Weight gain

Antidepressant

Alpha2

block

Pharmacologic Effects Of Antidepressants

Comparative Pharmacokinetics

Drug Interactions

• Newer antidepressants and CYP P450 inhibitory enzymes

Algorithm for the Treatment of Major Depressive Disorder

SSIR, SNRI or other (MRT, BUP)

Add psychotherapyAt any time

Partial or no response at 4-6 weeks at adequate dose

ReassessDiagnosisOptimize treatmentInadequate Response

at 4-6 weeks

Switch to new antidepressantfrom different class

Augment treatment with:1 Lithium2 Atypical antipsychotic3 Lamotrigine4 Thyroid hormone

Combine two antidepressants from different classes

Consider ECT at any time, especially ifVery severe MDD, not eating, catatonia, psychotic delusions, suicidal,

pregnant

Treatment

Psychotherapy

Medication

TCA

MAOI

SSRIs

Dual Reuptake Inhibitors

Drugs with Novel

Mechanism

Benzodiazepine (Adjunctive Therapy )

Electro-convulsive Therapy ECT

Electroconvulsive Therapy (ECT)Electroconvulsive therapy (ECT) is very safe and effective for treating depression. ECT is usually reserved for refractory or psychotic patients• Ranges from 6-12 treatments every other day

Special Populations

Pregnancy1) Treatment

a) Mild depression—psychotherapyb) Severe depression with decreased oral intake, suicidality,

or psychosis—pharmacotherapy or electroconvulsive therapy (ECT)

2) Antidepressants of choicea) Well-studied during pregnancy (tricyclic antidepressants

[TCAs])b) Short-acting (sertraline)

Special populations

• Elderly1. Treatment considerations

a) Pharmacokinetic and pharmacodynamic changesb) Coexisting medical conditions (e.g., cardiovascular disease)c) Anticholinergic side effectsd) Depression-related cognitive dysfunction (pseudo-

dementia)

2. Agents of choicea) Short-acting selective serotonin reuptake inhibitors (SSRIs)b) Bupropion, mirtazapine

Concurrent medical disorders

• Asthmaa) Avoid monoamine oxidase inhibitors (MAOIs) which interfere with

sympathomimetic bronchodilators

• Cardiac diseasea) Ventricular arrhythmia, subclinical sinus node dysfunction, conduction

defectsb) Avoid TCAsc) Use bupropion, SSRIs or ECTd) MAOIs do not affect cardiac conduction, rhythm, or contraction but

may induce orthostasis

Concurrent medical disorders

• Dementiaa) Avoid TCAs or antidepressants with

anticholinergic properties• Epilepsy

a) Avoid bupropion, TCAs• Glaucoma (narrow-angle)

a) Avoid TCAs

Concurrent Medical Disorders

• Hypertensiona) TCAs b) Concurrent antihypertensive treatment,

especially with diuretics, increases likelihood that TCAs, MAOIs, or trazodone will induce orthostasis

c) β-blockers may cause depression (?)• Parkinson’s disease

a) Avoid amoxapine (dopamine-receptor blocker)

Patient Education• Treat the patient with the same empathy, respect, and concern that you would

treat a patient with a medical illness

• Do not be afraid to discuss the symptoms of depression

• Be sensitive to the patient’s fear of being stigmatized

• Emphasize the common occurrence of depression as well as the many successful treatment options

• Compare depression to a common and accepted medical illness (e.g., diabetes or hypertension)

• Compare the need for medication compliance with antidepressants to the need for compliance with other maintenance medications (e.g., insulin or antihypertensive agents).