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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
ANTIDEPRESSANT MEDICATION
ANTIDEPRESSANT MEDICATION
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
ANTIDEPRESSANT MEDICATION
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
Possible Adverse Effects of Reuptake Blocking of Antidepressant Drugs*
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.
Tricyclic Antidepressants
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.
Tricyclic Antidepressants
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.
Tricyclic Antidepressants
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).
ANTIDEPRESSANT MEDICATION
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.
ANTIDEPRESSANT MEDICATION
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
ANTIDEPRESSANT MEDICATION
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.
ANTIDEPRESSANT MEDICATION
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
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
ANTIDEPRESSANT MEDICATION
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.
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 inhibitors
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.
ANTIDEPRESSANT MEDICATION
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!