Major Depressive Disordered I

Major Depressive Disordered I

Jawza F. Al-Sabhan, Msc. College of Pharmacy

Clinical Pharmacy Department

Mood Disorder

IntroductionEveryone experiences variations in mood, blues that come and go, disappointments, the normal grief that accompanies the loss of someone you love. But a severe or prolonged depression that interferes with the ability to function or feel pleasure is not a mere

case of the blues. It is an illness.

Depression affects many people of all ages.

It is the 8th leading cause of death for males, and 19th leading cause of death for females.

Epidemiology

Lifetime incidence of depression is 13-20%.

Life time incidence of depression in KSA 17%.

Life time prevalence 5-12%(US,Europe)

Most common age is late 20s.

Pathophysiology hypotheses

Biogenic amine1. Central nervous system (CNS) deficiency in dopamine,

norepinephrine, and/or serotonin

2. Based on knowledge that antidepressants increase monoamine neurotransmission

PermissiveAn underlying deficiency of serotonin accompanied by

decreased noradrenergic transmission

Pathophysiology hypotheses

Neuroendocrine finding 1. Pituitary and adrenal glands are enlarged in depressed

patients, and hypothalamic function may be abnormal.

2. Serotonin exerts a strong influence on HPA axis.

3. Approximately 45% to 60% of patients with major depression have a neuroendocrine abnormality, including hypersecretion of cortisol

NORADRENERGIC TRACTS

Noradrenaline, a key neurotransmitter involved in the control of mood and emotional behavior, is believed to inhibit or stimulate a variety of emotional responses such as anxiety, aggression, stress, and sleep

SEROTONERGIC TRACTS

Serotonin is involved in the regulation of pain, pleasure, anxiety, panic, appetite , and sleep behavior (the sleep-wake cycle).

Risk factors

1. Family history of depressiona. 1st degree relative of patients with depression are 1.5 to 3 times

more likely to develop depressionb. Twin studies

• Monozygotic twins have a 65% concordance rate for depression

• Dizygotic twins have a 14% concordance rate for depression

2. Female gender3. Previous depressive episode4. Chronic medical illness5. Substance abuse

Diagnostic Criteria (DSM-IV)for MDD

1. At least 5 symptoms present for 2 weeks most of day nearly every day2. Represents change from previous functioning

a. Depressed mood*b. Loss of interest or pleasure*c. Appetite or weight changed. Sleep disturbancee. Psychomotor agitation/retardationf. Fatigue/loss of energyg. Feelings of worthlessness/guilth. Decreased concentration/indecisivenessi. Recurrent thoughts of death/suicidal ideation/suicide attempt

3. Symptoms cause social or occupational impairment4. Symptoms are not due to substance abuse or medical condition5. Symptoms are not due to gereavement

Depression Sub-classification

A-Melancholia (endogenous)1. Weight loss2. Early morning awakening3. Extreme listlessness4. Intense guilt5. Inability to cheer up even for a

moment

B- Psychotic (or delusional)1. Mood congruent2. Poverty, physical illness,

moral transgressions3. Occur in 10–25%

C-Atypical depression (exogenous)1. Increased appetite2. Weight gain3. Excessive sleep4. Leaden sensation in the arms

and legs5. Mood reactive

D-Postpartum Depression1. Onset of depression

within 4 weeks2. occurs in 10% to 26%

Specific features of diagnosis

1) Milda) 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

Assessing Depression

Rating scales

Hospitalization Prognosis

Laboratory studies

Target symptoms

Assessing Depression

Target symptoms

D — depressed moodS — sleepI — interestG — guiltE — energyC — concentrationA — appetiteP — psychomotorS — suicide

Laboratory studies

There are no diagnostic lab tests for depression, although the following should be obtained to rule out other medical illnesses which mimic depression

a. Complete blood count (CBC; i.e., anemia)

b. Thyroid function tests (TFTs; i.e., hypothyroidism)

c. Rapid plasma reagin (RPR; i.e., syphilis)

d. Urine drug screen (i.e., substance abuse)

Prognosis

1. 70% of patients are responsive to antidepressant therapy2. Relapse

a. Following 1st episode, 50% experience another episodeb. Following 2nd episode70% experience another episodec. Following 3nd episode 90% experience another episode

Hospitalization

1. Patients who lack capacity to cooperate with treatment

2. Patients at risk for suicide or other violent behavior

3. Patients who lack psychosocial supports

4. Patients who have other psychiatric or general medical problems.

Rating scales

General purposea. Brief Psychiatric Rating Scale (BPRS), investigator-ratedb. Hopkins Symptom Checklist (SCL-90), patient-rated

Disease-specific rating scales (depression)a. Investigator-rated1) Hamilton Rating Scale for Depression (Ham-D, HRSD)2) Montgomery-Asburg Depression Rating Scale (MADRS)b. Patient-rated1) Beck Depression Inventory (BDI)2) Zung Self Rating Scale

Treatment Goals

Treatment

Electroconvulsive therapy

Medication and

psychotherapy

Medication

Psychotherapy

ChoicesOf

Treatment

Choices of Treatment

Psychotherapy

a. Less severe

b. Less chronic

c. No psychotic

d. Past positive response

e. Medical contraindication to medications

Medication

a. More severe

b. Chronic

c. Recurrent

d. Psychotic

e. Melancholic

f. Past positive response

g. Family history

h. Failure to respond to psychotherapy

Choices of Treatment

Medication and psychotherapy

a. More severe

b. Chronic

c. Partial response to either therapy alone

d. Personality disorder

Electroconvulsive therapy

a. Psychotic

b. Severe or extremely severe

c. Past positive response

d. Failure of several medications or combined treatment trials

e. Need for rapid response

f. Medical contraindications to medications

Antidepressant therapy

Initiation of therapy1. Initiate therapy with divided doses to minimize

adverse drug reactions

2. Consider age of patient and adjust accordingly

3. Target dose should be achieved as quickly as tolerated

4. Improvement in 3–4 weeks of therapy

5. Maximal response in 8 weeks of therapy

Phases of Treatment

Continuation

treatment

Maintenance treatment

Acute

treatment

Acute treatment

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

a) Definitioni) Complete (> 50% reduction)ii) Partial (> 20% but < 50%)iii) No response (< 20%)

b) Rate of responsei) First week• Decreased anxiety• Improvement in sleep• Improvement in appetiteii) 1–3 weeks• ↑ Activity, sex drive, self-care,

memory• Thinking and movements normalize• Sleeping and eating patterns

normalizeiii) 2–4 weeks• Relief of depressed mood• Less hopeless/helpless• Thoughts of suicide subside

Continuation treatment

1. To prevent relapse

2. Continue antidepressant 6–9 months after 1st episode at same dose

3. Continue with the same treatment and the same dose in acute phase.

Maintenance treatment

1. 1 year duration2. Use full therapeutic doses3. Goal is to prevent new episode (recurrence)4. Potential candidates

a) Three episodes of MDD orb) Two episodes of MDD and:

i) Family history of borderline personality disorder/recurrent MDD in 1st degree relative

ii) Recurrence within 1 year after medicine discontinuediii) Onset before age 20 or after age 60iv) Severe, sudden or life threatening depression

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

Class DrugDoseNo per packCostCost/month

TCAImipramine10 mg 60 tablets 16.80 SR100 mg

84 SR

TCAClopimramine25 mg30 Capsules28 SR100 mg

112 SR

SSRIFluvoxamine100 mg 30 tablets92 SR92 SR

SSRIEscitalopram10 mg 28 tablets117 SR125 SR

SSRICitalopram20 mg 28 tablets122 SR130 SR

SSRIFluoxetine20 mg 28 tablets122 SR462 SR

Novel Duloxetine60 mg 28 Capsules179 SR191 SR

DualMirtazapine30 mg 30 tablets177 SR 265.5 SR

DualVenlafaxine150 mg14 capsules135 SR289 SR

ANTIDEPRESSANT MEDICATION: REVIEW

ANTIDEPRESSANT MEDICATION

Antidepressants can be classified in several ways, including by chemical structure and the presumed mechanism of antidepressant activity.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 = Mono- Amines Oxides Inhibitor

3. SSRI = Selective Serotonin Reuptake Inhibitor

4. SNRI = Serotonin Reuptake Inhibitor


Tricyclics “TCAs”Amitriptyline 50 –300 mg/dayClomipramine 50 –250 mg/dayDoxepin 25 –300 mg/dayTrimipramine 50 –300 mg/day Imipramine 50 –300 mg/dayDesipramine 50 –300 mg/dayNortriptyline 25 –150 mg/dayProtriptyline 10 – 60 mg/day

Tertiary amines

Secondary amines

Mechanism Of Tricyclic Antidepressants TCA


TricyclicsBlock 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

Possible Adverse Effects of Reuptake Blocking of Antidepressant Drugs*

Serotonin Reuptake Blocking

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


Nor epinephrine

Reuptake

Blocking

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

Tremors, Increased arousal and Insomnia

Tachycardia

Raised blood pressure

Blockade of antihypertensive effects

Possible Adverse Effects of Receptor Blocking of Antidepressant Drugs*

Blocking

Muscarinic

Receptors

Dry mouth, Constipation, Urinary retention

Sinus tachycardia

Blurred vision

Attack or exacerbation of narrow-angle glaucoma

Cognitive impairment

Memory dysfunction

Blocking

Histamine 1 Receptors

Night-time sedation

Impairment of psychomotor coordination during the

daytime, Drowsiness

Weight gain

Potentiation of central depressant drugs

Tricyclic Antidepressants

Managements of Anticholinergic side effects.

Impaired visual accommodation may be counteracted through the use of pilocarpine eye drops.

Urinary hesitation may be treated by prescribing bethanechol, 200 mg/day

Dry mouth may be counteracted by advising the patient to use sugarless gum or candy or by prescribing an oral rinse of 1% pilocarpine used three or four times daily.

Constipation is best dealt with through adequate hydration and the use of bulk laxatives.


SedationTCAs also have affinity for histaminergic receptors and produce varying degrees of sedation.

In general, tertiary amines cause greater sedation, whereas secondary amines cause less.

Patients with major depressive disorder with insomnia may benefit from sedation when their medication is given as a single dose before bedtime.


Weight gain.TCAs have the capacity to induce weight gain possibly through their histaminergic properties.

The degree of weight gain appears to vary by agent (e.g., greater weight gain with amitriptyline and less with desipramine), be dose dependent, and be reversible with cessation of tricyclic antidepressant therapy.


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

Amoxapine, a TCA with antipsychotic properties, can also cause extrapyramidal side effects and tardive dyskinesia.

In overdoses, tricyclic antidepressants can precipitate seizures especially (Maprotiline).


Monoamine oxidase irreversible, non

selective inhibitors “MAO Is”Phenelzine 15 –90 mg/day

Tranylcypromine 10 – 60 mg/day

Inhibit the enzymatic breakdown of 5HT and NE.

They are usually reserved for atypical or resistant depression

due to their toxicity profile.


Reversible monoamine oxidase

inhibitors ”RIMA”Moclobemide

This unique mechanism results in a good tolerability profile and unlike traditional MAOIs, there is no need to restrict dietary tyramine.

Monoamine oxidase inhibitors

Hypertensive crises.A hypertensive crisis can occur when a patient taking an MAOI ingests large amounts of tyramine or other pressor amines in foods or medications.

This reaction is characterized by the acute onset of severe headache, nausea, neck stiffness, palpitations, profuse perspiration, and confusion, possibly leading to stroke and death.

Monoamine oxidase inhibitors

Hypertensive crises.Dietary restrictions include avoiding such foods as aged cheeses or meats, fermented products, yeast extracts

The list of medications that must be avoided includes all sympathomimetic and stimulant drugs as well as over-the-counter decongestants and cold remedies.

Monoamine Oxidase Inhibitors

Cardiovascular effects.Orthostatic hypotension is commonly seen during MAOI treatment.

Possible treatments for this side effect include the addition of salt to increase intravascular volume or use of the steroid fludrocortisone.

MAOI use can also be associated with the development of peripheral edema, which may be helped by the use of support stockings.

Major Depressive Disordered II

Jawza F. Al-Sabhan, Msc. College of Pharmacy

Clinical Pharmacy Department

COMPARATIVE EFFICACY

SSRIs have a flat dose-response curve. There is seldom any advantage in dosing higher than the usually effective minimum dose.

TCAs, and other atypical antidepressants appear to have an ascending dose-response curve, thus higher doses are usually associated with increased efficacy.

COMPARATIVE SAFETY

Most current literature considers the SSRIs to be better tolerated than TCAs, especially when used at the minimally effective dose.

One meta-analysis has disputed this, arguing that dropout rates (~32%) are not significantly different for either group.


Selective serotonin reuptake inhibitors “SSRIs”

Fluoxetine 20–40mg/day

Sertraline 50 –200 mg/day

Paroxetine 20–40 mg/day

Fluvoxamine 50 –300 mg/day

Citalopram 20 – 40 mg/day

Escitalopram 10-20 mg/day

Mechanism of SSRI


Serotonin Reuptake Blocking

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


Selective Serotonin Reuptake InhibitorsBlock the reuptake of 5HT and increase synaptic 5HT transmission.

They have little or no effect on other neurotransmitters, results in fewer anticholinergic (ACH) and sedative effects.

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.


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.


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.


Effects on weight.

Fluoxetine has been shown to cause an initial reduction in weight but this tends be gained back subsequently.

The literature differs as to whether patients taking SSRIs beyond the acute phase do or do not experience weight

gain as a medication side effect.

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.


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, but unlike mianserin it has no significant effect on the synaptic reuptake of catecholamines.

MIRTAZIPINE SIDE EFFECTS

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

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

Although agranulocytosis has been observed to occur in patients taking mirtazapine.

VENLAFAXINE

Venlafaxine is selectively inhibits neuronal uptake of serotonin, norepinephrine.

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

BUPROPION

Bupropion is a very weak inhibitor of norepinephrine uptake and a weak inhibitor of dopamine uptake.

Side effect including headaches, tremors, and seizures.

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

AntidepressantAntidepressant

Alpha2

block

Pharmacologic Effects Of Antidepressants

Algorithm for Treatment Major Depressive Disorder.

Electroconvulsive Therapy ECT

MECHANISM OF ECT

Electroconvulsive therapy involves applying a brief electrical pulse to the scalp while the patient is under anesthesia. This pulse excites the brain cells causing them to fire in unison and produces a seizure.

Cont. ECT

Nursing staffPsychiatrist Anesthesiologist

Cont. ECT

Bilateral PlacementRight Unilateral Placement

Comparative Pharmacokinetics

Drug Interactions

Newer antidepressants and CYP P450 inhibitory enzymes

Drug Interactions

TCAsa) TCA + anticoagulant → ↑ anticoagulant effect

b) Enzyme inhibitors → ↑ TCA effect

c) Enzyme inducer → ↓ TCA effect

d) TCA + centrally-acting antihypertensive → ↑ BP

e) TCA + sympathomimetic → ↑ BP plus arrhythmias

f) TCA +MAOI → hypertensive crisis

Drug Interactions

MAOIs

a) MAOI + stimulant → hypertensive crisis

b) MAOI + antidiabetics → hypoglycemia

c) MAOI + insulin → hypoglycemia

d) MAOI + levodopa → hypertensive crisis

Drug Interactions

SSRI a) SSRI + TCA → ↑ TCA effect

b) SSRI + carbamazepine → ↑ carbamazapene

d) SSRI + antipsychotic → ↑ antipsychotic effect

e) SSRI + warfarin → ↑ bleeding time

f) SSRI + MAOI → serotonergic syndrome

Special Populations

Pregnancy

1) Treatmenta) Mild depression—psychotherapy

b) 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], fluoxetine)

b) Short-acting (sertraline, paroxetine)

Special populations

Lactation1) Antidepressants of choice

a) Well-studied (?)b) Improved pharmacokinetic profilesc) Limited metabolitesd) Greater receptor selectivity

2) Specific agentsa) Sertraline, paroxetineb) Nortriptyline, desipramine

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

Concurrent medical disorders

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

sympathomimetic bronchodilators

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

defects

b) Avoid TCAs

c) Use bupropion, SSRIs or ECT

d) MAOIs do not affect cardiac conduction, rhythm, or contraction but may induce orthostasis

Concurrent medical disorders

Dementiaa) Avoid TCAs or antidepressants with

anticholinergic properties

Epilepsya) Avoid bupropion, maprotiline, amoxapine, TCAs

Glaucoma (narrow-angle)a) Avoid TCAs

Concurrent Medical Disorders

Hypertensiona) TCAs may antagonize the therapeutic actions of

guanethidine, clonidine, or methyldopa

c) Concurrent antihypertensive treatment, especially with diuretics, increases likelihood that TCAs, MAOIs, or trazodone will induce orthostasis

d) β-blockers, esp. propranolol may cause depression

Parkinson’s diseasea) 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).

Thank god for his mercy,who carry a hope for us with every sunrise!

Major Depressive Disordered I

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