Antidepressants work through multiple mechanisms including increasing monoamines like serotonin, norepinephrine, and dopamine; increasing brain-derived neurotrophic factor (BDNF); and decreasing corticotropin-releasing hormone (CRH). The main classes of antidepressants are SSRIs, SNRIs, NDRIs, NRIs, SARIs, SPARIs, TCAs, and MAOIs. Treatment goals have shifted from response to remission and recovery, though residual symptoms often persist even with response.

1. Mechanism of Action
Classes of Antidepressant
Medications
Clinical Effects and Side Effects

2. Things I always wanted to know about
depression, but I forgot I did not know

3. Response = 50% improvement of
symptoms
 In the past decades the goal of treatment in
depression was a response.
 Now the goal of treatment in depression is
remission and recovery.

4. Remission vs. Recovery
 Remission: Patient is symptom free for 4-9
months.
 Recovery: Patient is symptom free for more than 12
months.

5. STAR*D Study
 In a large NIMH study called Sequenced Treatment
Alternatives to Relieve Depression(STAR*D) the goal
of treatment was remission.
 Only 1/3 of patients on Citalopram monotherapy
remitted.
 2/3 of patients failed to remit to Citalopram alone.
 If we are talking response instead of remission – 60-
70% of patients respond to SSRI monotherapy.

6. Relapse vs. Recurrence
What is a relapse? – Getting worse during the remission phase
What is a recurrence? – Getting worse during recovery phase

7. Remission rates in MDD
Approximately one-third (33%) of depressed patients will remit during
treatment with any SSRI monotherapy.
Unfortunately, for those who fail to remit, the likelihood of remission
with another antidepressant monotherapy goes down with each
successive trial. Thus, after a year of treatment with four sequential
antidepressants (from four different classes) taken for twelve weeks
each, only two-thirds of patients will have achieved remission.

8. Common residual symptoms
In patients who do not achieve remission(but achieve response), the
most common residual symptoms are insomnia, fatigue, painful
physical complaints, problems concentrating, and lack of
interest. The least common residual symptoms are depressed
mood, suicidal ideation, and psychomotor retardation.

9. Antidepressants - Actions

10. Antidepressants: complex drugs
 These are the known mechanisms through which antidepressants exert
their actions:
1. Increase in monoamines
2. Increase in BDNF
3. Decrease in CRH
4. Increase of neurogenesis in hippocampus
5. Methylation of DNA(epigenetic factors)
6. Increase secretion of GDNF in glial cells

11. Monoamine Hypothesis
 Depression is due deficiency of monoamines:
serotonin, dopamine or norepinephrine

12. All antidepressants (except MAO inhibitors) block
monoamine transporter proteins
 Serotonin Transporter(SERT)
 Norepinephrine Transporter(NET)
 Dopamine Transporter(DAT)

13. In the Prefrontal Cortex Blocking NET Increases both
Norepinephrine and Dopamine
 In the human prefrontal cortex there are very few DAT.
 As a result dopamine diffuses outside of the synapse, accumulates in
the prefrontal cortex and is eventually disposed of by NET.
 Thus drugs that block NET increase both Norepinephrine and
Dopamine in the prefrontal cortex.

14. What is Neurotrophin Hypothesis?
 The reason why antidepressants work may not be the
fact that they increase serotonin, dopamine or
norepinephrine, but BDNF.
 BDNF is produced by the neurons and is encoded by a
gene on chromosome 11.

15. BDNF Increases Dendritic Spines

16. Actions of BDNF
-Sustains the viability of neurons (neuroprotection)
-Increases dendritic arborization and
the number of synapses.
-BDNF gene is suppressed by stress
(via cortisol).
-Decreased BDNF levels lead to
neuronal atrophy and neuronal death.
- BDNF levels are low in depression,
but increase with antidepressant treatment.
- Exercise increases BDNF levels.

17. Low BDNF - depressed mood and
suicidal behavior

18. Antidepressant Classes
 Serotonin Selective Reuptake Inhibitors(SSRIs)
 Serotonin Norepinephrine Reuptake Inhibitors(SNRIs)
 Norepinephrine and Dopamine Reuptake
Inhibitors(NDRIs)
 Selective Norepinephrine Reuptake Inhibitors(NRIs)
 Alpha 2 Antagonists as serotonin and norepinephrine
Disinhibitors(SNDIs)
 Serotonin Antagonist/Reuptake Inhibitors(SARIs)
 Serotonin Partial Agonist Reuptake Inhibitor (SPARI)
 Tricyclic Antidepressants(TCA)
 Monoamine Oxidase Inhibitors(MAOI)

19. Psychopharmacologically speaking there are
only two classes of depressions

20. Serotonin Selective Reuptake
Inhibitors (SSRIs)
 Six agents are in this class:
Fluoxetine, Paroxetine, Sertaline, Fluvoxamine, Citalopram
and Escitalopram.
 Fluvoxamine does not have an FDA indication for
depression. It was approved for social phobia and OCD. In
other countries it is being used for depression.
 Three agents come in CR form: Fluoxetine, Paroxetine and
Fluvoxamine.
 All are generic except the CR preparations.

21. SSRIs overview
Efficacy(FDA approved) for:
 MDD (all except Fluvoxamine)
 OCD( all except Citalopram and Escitalopram)
 Social Phobia(Sertaline, Fluvoxamine, and Paroxetine)
 PTSD(Sertaline and Paroxetine)
 Bulimia(Fluoxetine)
 GAD(Paroxetine and Escitalopram)
 PMDD(Fluoxetine, Paroxetine CR and Sertaline)
 Side Effects: GI, decreased libido, delayed
ejaculation, headaches and Insomnia/Somnolence.

22. Serotonin Norepinephrine
Reuptake Inhibitors(SNRIs)
Four agents: Venlafaxine, Desvenlafaxine, Duloxetine and
Milnacipran
Efficacy(FDA approved) for:
-Venlafaxine(MDD, GAD, Social Phobia)
-Desvenlafaxine(MDD)
-Duloxetine(MDD, GAD, neuropathic pain, fibromyalgia)
-Milnacipran(fibromyalgia)
Off label uses:
Venlafaxine (ADHD)
Duloxetine (stress urinary incontinence)
Desvenlafaxine(vasomotor symptoms associated with
menopause)

23. Norepinephrine and Dopamine
Reuptake Inhibitors(NDRIs)
 One drug: Bupropion
 FDA indication: MDD, smoking cessation and SAD.
 Off label use: depression in cardiac patients, adjunct to
SSRIs (for depressed mood as well as to counteract sexual
side effects), substance abuse problems, ADHD and weight
loss.
 Mechanism of Action: mild dopamine reuptake
inhibitor, norepinephrine reuptake inhibitor (via its
metabolite hydroxybupropion).
 Adverse effects: 4/1000 risk for seizure disorder in
immediate-release formulations (doses higher than 450
mg/day) and 1/1000 in sustained release
formulations(identical to all other antidepressants).

24. Selective Norepinephrine Reuptake
Inhibitors(NRIs)
 Two drugs: Atomoxetine and Reboxetine(not
approved in US).
 Mechanism of Action: Block norepinephrine
transportes. In the prefrontal cortex there are very few
dopamine transporters. Norepinephrine transporters
dispose of both norepinephrine and dopamine. For
this reason when the norepinephrine transporters are
blocked the levels of both NE and DA are increased.
 Atomoxetine (Strattera) has the FDA indication for
ADHD, but off label it is used as antidepressant.

25. Alpha 2 Antagonists as Serotonin and
Norepinephrine Disinhibitors(SNDIs)
 One drug: Mirtazapine
 FDA indication: MDD
 Off label uses: panic d/o, GAD, negative symptoms of
schizophrenia, anti-nausea medication in chemotherapy
patients(Kim 2008)and post operative nausea(Chen 2008).
 In STAR*D trial the combination of Mirtazapine(average
dose 36 mg/day) with Venlafaxine (average dose 210
mg/day) resulted in remission of 13% of patients who failed
three consecutive antidepressant trials(McGrath 2006).
 Mechanism of action: Blocks alpha 2 adrenergic
receptors presynaptically(autoreceptors) on
noradrenergic and serotonergic neurons, leading to
disinhibition of serotonin and norepinephrine. In
addition, mirtazapine blocks 5HT2A, 5HT2C and 5HT3
postsynaptically.

26. Serotonin Antagonist/Reuptake
Inhibitors(SARIs)
Two agents: Trazodone, Nefazodone
Both have FDA indication for MDD.
Off label use:
anxiety (Trazodone),
PTSD (Nefazodone one of the most prescribed drugs for PTSD).
Depression with co-morbid substance abuse (Nefazodone).
Mechanism of Action: presynaptically blocks the serotonin
transporters and 5HT1A
postsynaptically blocks 5HT2A, 5HT2C
Adverse effects: liver damage (risk 1/250,000 per patient/year) =
If a quarter of a million patients were taking Nefazodone for a
year , one patient would be expected to develop liver damage.

27. Serotonin Partial Agonist Reuptake
Inhibitor (SPARI)
 Vilazodone (Viibryd) approved in January 2011.
FDA approved for Major Depressive Disorder
Off label used for Anxiety
 Mechanism of action:
-blocks serotonin reuptake pumps
-partial agonist at presynaptic somatodendritic 5HT 1A
Dosage:
40 mg once daily with food (taken on empty stomach 50%
reduced absorbtion
Side effects: nausea, diarrhea, insomnia, rare hyponatremia

28. Tricyclic Antidepressants(TCA)
 Efficacy: Second or third line agents for MDD,
Panic d/o, OCD (FDA approved Clomipramine), Pain
Syndromes, Migraine prophylaxis, Enuresis (FDA approved
Imipramine).
 Side Effects: dry mouth, urinary
retention, constipation, blurred vision, confusion, weight
gain, sedation, sexual dysfunction, orthostasis, tachycardia and
cardiac conduction abnormalities.
 Drug interactions: TCA increase warfarin levels, cimetidine
increases TCA levels, clonidine – hypertensive crises(avoid), oral
contraceptives – increase TCA levels, SSRIs increase TCA
levels, quinidine with TCA- increase in arrhythmias(avoid), L-
dopa decreases TCA levels, sympathomimetics with TCAs – risk
for arrhythmia, HTN, tachycardia.

29. MAO Inhibitors (MAOI)
 Efficacy: Third line agents for MDD, second line for
Parkinson’s disease(Selegiline).
 FDA indications: treatment resistant depression.
Selegiline(Emsam) was approved by the FDA in 2006 in the transdermal
form for depression (oral Selegiline is not approved for depression).
The Selegiline dilemma: Selegiline is a MAO-B inhibitor and in the doses
used for Parkinson’s disease (5-10 mg a day) has a low risk for hypertensive
crises. Unfortunately for the treatment of depression higher doses (40-60
mg a day) are needed. At these high doses the drug affects both MAO-A
and MAO-B and the risk for hypertensive crises is high.
The transdermal Selegiline(Emsam) bypasses the gut and the liver and thus
allows for use of higher doses with lower risk for hypertensive crises(below
60 mg a day).

30. Drug Interactions and Adverse
Effects
 Risk of serious drug interactions is limited with SSRIs, except in two
circumstances:
 -Fatalities have been reported from serotonin syndrome when used in
close proximity with MAOI, even if the drugs were not used
concurrently.
 -Inhibition of 2D6 enzyme by the SSRIs.
Many drugs are metabolized by this enzyme, including TCA, type 1C
antiarrhythmic agents, some beta blockers, benztropine and many
antipsychotics.
SSRIs inhibit 2D6, leading to increased plasma levels of other agents (8
fold increase in TCA plasma levels have been reported when used
together).

31. Antidepressants During Pregnancy
(damned if you do, damned if you don’t)

32. T3/T4 augmentation of antidepressants
(in thyroid deficiency)

33. Lithium increases the efficacy of
antidepressants(lithium augmentation)

34. L-5-methyl-tetrahydrofolate(MTHF)
 MTHF(unlike folate) crosses the BBB and activates the enzymes that
lead to the formation of NE, DA and 5HT.
 These are the rate limiting enzymes such as triptophan
hydroxilase(5HT)and thyrosine hydroxilase(DA and NE).

35. Vagus Nerve Stimulation
 The vagus nerve connects with the neurotransmitter centers in the
brainstem(locus coeruleus and raphe nuclei).
 A pacemaker -like device is implanted in the chest wall with an implanted lead
wrapped around the vagus nerve in the neck area.
 The device delivers pulses to the vagus nerve, which in turn boost monoamine
neurotransmission.

36. Transcranial Magnetic Stimulation(TMS)
 Rapidly alternating current passes through a small coil placed over the scalp.
 This generates a magnetic field that induces an electrical current in the DLPFC.
 The affected neurons then signal other areas of the brain VMPFC and
amygdala, giving a triaminergic boost.

37. Deep Brain Stimulation
 Effective for the treatment of motor complications in Parkinson’s disease and is now
used in some centers for treatment resistant depression.
 Consists of a battery -powered pulse generator implanted in the chest wall like a
pacemaker.
 One or two electrodes are implanted into the subgenual area of ACC .

38. Putative New Generation
antidepressants
 Corticotropin-Releasing Hormone Receptor
Antagonists(CRH1, CRH2)
 Vasopresin Receptor Antagonists(V1A, V1B)
 Glucocorticoid Receptor Antagonists(GR, MR)
 Agomelatine
 Glutamate Blockers(AMPA blockers, NMDA blockers)
 Neuropeptides(substance P, Galanin, Orexigenic
Peptides)
 GSK 3 inhibitors
 Neurogenesis Enhancers(BDNF, GDNF)
 Beta 3 agonists

39. Glucocorticoid Receptor Antagonists
 Several reports suggested that Mifeprestone (RU-486)
was beneficial in MDD with psychotic features
(DeBattista et al. 2006)

40. Agomelatine

41. Beta 3 Agonists

42. Ketamine and other Glutamate Blockers
 Ketamine 0.5 mg/Kg intravenously administered to patients with major
depression was found to exert a rapid (2 hours) postinfusion antidepressant
effect lasting about a week(Zarate et al. 2006).

43. References:
 Stahl’s Essential Psychopharmacology, Third
Edition, 2010
 Textbook of Psychopharmacology, Fourt
Edition, Schatzberg, Nemeroff, 2010
 Brain Protection in Schizophrenia, Mood and
Cognitive Disorders, Ritsner et al, 2010