Pharmecotherapeutics

of Depression

By Jitesh Chawla, MD

12/23/2004

G&O

• Goal: Learn about different pharmacological treatments for depression and how to use them

• Objectives: 1. Review significant differences in SSRI drugs (first-

line agents), indications for use

2. What to do when first-line agents don’t work.

3. Discuss the side effects, indications, dosages, effectiveness for second-line agents

4. Introduce the use of augmentation agents

5. Learn to combine, switch and discontinue these drugs

Hypotheses of Depression

• Mononamine: Depression is caused by deficiency of neurotransmitters (NE, serotonin, dopamine)

• Neurotransmitter Receptor: Abnormality in receptor function, due to up-regulation

• Gene expression: Problem with signal transduction to post-synaptic neuron with normal amounts of monoamines and receptors1

Serotonin Physiology

• Initially, inhibition of serotonin reuptake increases levels at somatodendritic areas more than pre-synaptic terminals

• Auto-receptors at somato-dendritic desensitize and axonal impulse to presynaptic areas increase

• Serotonin released but after few weeks receptors at post-synaptic terminals down-regulate

Serotonin Physiology Cont’d

Reference1

Serotonin Physiology Cont’d

Reference1

Serotonin Physiology Cont’d

• Serotonergic projections to:

– Frontal cortex : mood

– Basal ganglia: akithesia and agitation

– Limbic: anxiety and panic

– Hypothalamus: appetite

– Brainstem: Sleep

– Spinal Cord: spinal reflexes in sexual orgasm

– 5HT 3 receptors in brainstem: vomiting

– 5 HT3 and 5HT4 in gut: abdominal; pain, diarrhea

SSRI drug class

• 1st line choice for depression currently

• Popular because other indications for use include

anxiety, eating disorders, OCD, phobias

• Common side effects: sexual dysfunction, GI problems,

agitation, weight gain

SSRI drugs: Fluoxetine

• Dosing :

– Start at 20 mg/d Most can maintain at 20-40mg/ d,

– some stable patients need only a 60-90mg single

dose per week.

– very intolerant of SE can start at 5mg/d

• Advantages: weight loss, effective in PMS

• Notable side effects: agitation, insomnia

• Cost: 10mg, 30 capsules $24.99

SSRI drugs: Paroxitine

• Dosing: - Start 20 mg/d, 10mg/d in elderly

– Titrate up to 50mg/d in 4 weeks if not response

– For concurrent panic disorder 60mg/d shown effective

• Advantages: slightly more calming effect, effective for anxiety

• Notable side effects: More constipation, weight gain, sexual dysfunction

• Cost: 10mg/30 tabs $74.99

SSRI Drugs: Sertaline

• Dosing: – Maintenance at least 100mg/d

– Start 50mg/d

– Max 200 mg/d

• Advantages: No weight gain

• Notable side effects: GI, particularly diarrhea

• Cost: 25mg/ 30 tab $73.78

SSRI drugs: Citalopram

• Dosing: – Start 20mg/d

– Most maintain at 20-40mg/d

– Reduce to 10mg/d if nausea bad

– Elderly can maintain at 20-40mg/d

• Advantages: Less sexual dysfunction, agitation

• Notable side effects: Nausea very common (but usually just when start) *Some may tolerate Lexapro better

• Cost: 10mg (generic)/30 tabs $39.99

Common reasons for failure

1. Inadequate dosage

2 . Inadequate length of therapy

3. Noncompliance (side effects, cost)

4. Pharmacologic Treatment resistant depression

5. Wrong Diagnosis

Length of Treatment

Latest studies show that within 6-12months of those having

an initial response half will relapse if the antidepressant is replaced

with placebo.

Reference: Handbook of Psychiatric Drug Therapy, 2000 Lippincott

Tricyclic Antidepressant

Pharmacology

• Three-ringed structure, highly lipophilic

• Blocks reuptake of NE, serotonin and less extent

dopamine

• Blocks muscarinic cholinergic- dry mouth, blurry vision,

constipation

• Blocks histaminergic- weight gain, drowsiness

• Alpha-1 blocking receptors-dizziness, orthostatic

hypotension

TCAs

• Used when first line agents (i.e. SSRIs )may not work

• Clinical effect is usually dose-related

• Imipramine start 25mg/d, amitriptyline start 50mg/d (QHS), lower in elderly, max 300mg/d

• High potential for toxicity (i.e. cardiac arrhythmias), monitor levels 10-14hrs after last dose and 5d after

• Highly effective for neuropathic, chronic pain

Comparsion Of Efficacy

• RCT of 471 adults beginning depressant drugs at

HMO in Seattle including desipramine, fluoxetine and

imipramine. Dosing, med changes, discontinuation

managed by PCP.

• Clinical effect on Depression measured by Hamilton

Scale, quality of life by SF-36 Health Survey and

medication use patterns gauged by interviews at

baseline and 6,9,12,18 and 24 months

• Results showed compliance higher for Prozac but no

difference in depression severity or quality of life

compared to TCAs3.

NE physiology

Reference. Handbook of Psychiatric Drug Therapy, 2000 Lippincott

NE Physiology Cont’d

Noradrenergic projections to:

– Brainstem: BP

– Frontal: (ß-1) mood, (A2 attention

– Limbic: emotion, agitation

– Cerebellar: tremor

– Bladder: Emptying via A1

Serotonin and Norepinephrine

• NE can diffuse to Alpha-2 receptors on serotonergic

neurons acting as a brake for further serotonin release

• But NE on alpha-1 receptors on the same neurons

causes further release of serotonin

Effexor:

• Pharmacology: At lower doses acts like SSRI

at higher also inhibits NE uptake

Lacks anti-cholinergic, --histaminergic,alpha-1blocking effects

• Dosing: start 37.5mg bid, increase much as q4d, usual maintenance 75-225mg /d, max 375mg/d

• Advantages: often effective in those with treatment failures on SSRIs or TCAs

• Notable Side Effects: Same as SSRI but more diaphoresis and at higher doses modest BP increase (5-7% of patients)

Wellbutrin:

• Pharmacology: phenylthylamine compound

structurally similar to amphetamines, lacks

anticholinergic properties, increases uptake

• Dosing: Start 100mg bid, can increase q3d,

maintain at 100mg tid as tolerated. Max 450mg/d (

higher doses risk of seizures)

• Advantages: Can be used as adjunct to tobacco

cessation, no sexual dysfunction, lower risk of

precipitating mania (small studies), better

concentration

• Notable Side Effects: Agitation, GI (soon after

starting), lowers seizure threshold, insomnia

Choices for Different Types of

Depression

• Bipolar : all agents have risk to precipitate mania but some studies show that Wellbutrin and SSRIs less likely than TCAS

• Atypical: MAOIs better response than TCAs. Prozac shown to be effective and SSRI safer than TCAs for this use.

• Psychotic features: TCAs with antipsychotics to be avoided because anticholinergic effects. SSRIs can increase extra-pyramidal effects and Zoloft and Celexa less likely than Prozac and Paxil

Combination Therapy

• Useful when patient has partial response to one

drug especially even at max doses and want to

dry another antidepressant

• Better to try drug with different mechanism of

action

• Drug interactions a concern. For example, MAOIs

shouldn’t be combined with SSRIs as risk of

serotonin syndrome

Augmentation

• Used to boost up effect of primary drug when partial response in seen

• Lithium 50% SSRI, TCA non-responders respond.

– Level .4mEq/L, Level 5-7d later

– minimally effective start 300mg bid-tid. Response seen generally in 2-3 weeks latest2. Efficacy-cited

study8 • T3 studies show help with TCA compared to SSRI

non-responders2.

– must be euythroid work well in women with fatigue and psychomotor retardation Start with 25-50mcg/d

– If effective will see partial response in 2 weeks with max in 4 weeks

Augmentation Cont’d

• Pindilol:

– shown in some studies show with 5HT1A antagonism

can elevate serotonergic activity

– given at doses 2.5 to 5mg tid

• Stimulants

– works by enhancement of dopaminergic,

noradrenergic neurotransmission.

– Dexedrine 2.5 to10mg bid

*Efficacy of both types of agents: Case report and

open studies9

Augmentation Cont’d

Buspar:

– SSRI augmentation strategy as its metabolite 1-PP

interacts with serotonergic neurons. helps with SSRI

sexual dysfunction.

– Started at 30-45mg QD dosages.

– Side effects are restlessness primarily with GI less

frequent

– Effectiveness: Few case report studies9

Switching

• Switching reasonable if NO response in 4 weeks (study

shown only 20% will respond if not switched) 6

• From one SSRI to another for non-response is effective5

• Try class with different mechanism of action

• Consider discontinuation principles always

Discontinuation

• Discontinuation Syndrome marked by nausea, vertigo, ataxia, paresthesias among other symptoms

• Whether to stop immediately or taper and need for a “wash-out period” depends on mechanism of action of drug

– SSRI to another SSRI safe switch without cross-

tapering except for Prozac7 – SSRI to Effexor safe but either to Wellbutrin taper

with wash-out of several days7 – TCAs better to taper to a low dose before stopping

– SSRI to nafezadone need for taper but no wash-out

Suicidality and Antidepressants

• TADS is a well-designed study containing 432 teens

followed for 2 years randomized to Prozac only, with

CBT, CBT only and placebo groups; monitored by

frequent office visits and questionnaires. Started in

2003

• The reported suicide-related adverse events in:

– 6.9% taking Prozac vs. 4% not taking it.

– NNH was 34 .

• Further, the number of reported suicide attempts was:

– 6 of 216 taking fluoxetine vs. 1 in 223 not taking it.

– NNH was 434

Non-pharmacological therapies

• Ward et al recruited patients from 24 practices in 2 major

English cities in 2000 for RCT comparing psychological

treatment of depression and use of pharmacological

therapy by MDs

• 67 patients got drug therapy, 63 cognitive behavior therapy

and 67 non-directive counseling. Uniformity of technique

monitored by randomly taping sessions. Outcomes

measured by Beck scale at 4 and 12 mos.

• Psychological therapy points showed better Beck scores

than drug treatment group initially but no difference at 12

mos. Those in counseling showed more satisfaction than

CBT per post-trial survey5

References

1. Handbook of Psychiatric Drug Therapy, 2000 Lippincott

2. Stahl, Stephan Essential Psychopharmacology of Depression and Bipolar Disorder 2000 Cambridge University press

3. Archives of Family Medicine Vol. 8 No.4

7/1999 “long-term outcomes of initial antidepressant drug choice in “real world”

4. Treatment for Adolescents with Depression Study JAMA. 2004; 292: 807-820

5 Walling, Anne. Psychological therapies vs. Physician Care for Depression American Family Physician July 2001

References Cont’d

6.Brown, Harrison Are pts who are tolerant to one serotonin selective reuptake inhibitor intolerant to another? J Clin Psychiatry 1995: 56: 30-34

7.Ferentz, Kevin Why, when and how to switch anitdepressants Patient Care 2004; 38 58-63

8. (lithium study) http://www.cpa-apc.org/Publications/Archives/CJP/2003/august/bauer.asp

9. Marangell LB. Augmentation of standard depression therapy. Clin Ther 2000;22(suppl A):A25-38.

More References Available If

Interested for Learning About

this Topic

• 1. Medical Letter

• 2. http://www.ahrq.gov/clinic/deprsumm.htm

• 3. Up to Date

• 4. Essential Psychopharmacology by Stephan

Stahl