1. Antidepressant update
WALID SARHAN

2. Antidepressants TCAs SSRIs doxepin TCAs MAOIs MAOIs MAOIs TCAs TCAs
isocarboxazide
MAOIs
TCAs
maprotiline
MAOIs
Venflaxine
Venflaxine
MAOIs
MAOIs
SSRIs
SSRIs
Amoxepine
SSRIs
Venflaxine
MAOIs
Nortriptyline
sarhan

3. Classification of Antidepressants
MAO-inhibitors; Monoamine Oxidase Inhibitors
e.g. tranylcypromine, moclobemide
TCA; Tricyclic Antidepressants
e.g. amitriptyline, clomipramine, desipramine, doxepine, imipramine
SSRI; Selective Serotonergic Re-uptake Inhibitors
e.g. paroxetine, fluvoxamine, fluoxetine and citalopram
NRI; Noradrenergic Re-uptake Inhibitors
e.g. reboxetine, (TCAs)
SNRI; Serotonergic and Noradrenergic Re-uptake Inhibitors
e.g. venlafaxine, milnacipran, (TCAs)
NaSSA; 2-Adrenoreceptor Antagonists
e.g. mirtazapine

4. Antidepressants
1. Tricyclic anti-depressants (TCAs). Imipramine, desipramine, nortriptyline, protryptyline, amytriptiline, doxepin. 2. Monoamine oxidase inhibitors (MAOIs). Isocarboxacid, phenelzine, tranylcypromine. 3. Selective serotonin reuptake inhibitors (SSRIs) Fluoxetine, sertraline, paroxetine, trazodone. 4. Atypical anti-depressants (Others) New TCAs, amoxapine, bupropion, alprazolam, maprotiline, nomifensine, mianserin.
sarhan

5. Tricyclic Antidepressants (TCAs)
amytriptiline
imipramine
desipramine
nortriptyline
protryptyline
doxepin.
sarhan

6. Tricyclic Antidepressants (TCAs)
Mechanism of Action:
- Inhibition of NT reuptake.
- Immediate action = > NE and 5-HT in synapse.
- After chronic treatment (2 - 4 weeks) = >
  NE-R and 5-HT2R.
 NE release and turnover.
 NE-stimulated cAMP in brain.
 Sensitization of 5-HT receptors.
* Adaptive Responses *
- Takes up to 4 weeks for all TCA antidepressants to have an effect.
sarhan

7. Tricyclic Antidepressants (TCAs)
Side Effects:
Atropine-like side effects: dry mouth, paradoxical excessive perspiration, constipation, blurred vision, mydriasis, metallic taste, urine retention => muscarinic blockade.
Orthostatic hypotension => 1-AR and possibly 2-AR blockade.
Drowsiness, sedation and weight gain => Histamine-Receptor blockade.
sarhan

8. Tricyclic Antidepressants (TCAs)
Side Effects (con’t):
Most serious side effect is cardiac toxicity => Palpitations, tachycardia, dizziness => excessive CNS stimulation => NE in Heart.
Sexual dysfunction, including loss of libido, impaired erection and ejaculation and anorgasmia
.  COMPLIANCE
sarhan

9. Cipralex-purlex-zelax Prozac, Faverin Seroxar-unirox Zoloft, solotik
Brands
SSRIs
Citalopram
Escitalopram
Fluoxetine
Fluvoxamine
Paroxetine
Sertraline
Cipram-lecital
Cipralex-purlex-zelax
Prozac,
Faverin
Seroxar-unirox
Zoloft, solotik
sarhan

10. SNRIs Brands Desvenlafaxine Duloxetine Venlafaxine Pristiq Cymbalta
Efexor
Remeron
Valdoxan
Mirtazapine (NaSSA)
Agomelatine
sarhan

11. Antidepressant Efficacy
Mood Disorders:
Major Depression
Dysthymia & Subthreshold depression
Bipolar Disorder (combined w Mood Stab)
Schizoaffective, depressed type
Anxiety Disorders:
OCD, Panic, GAD, PSTD
Impulse Control Disorders:
Klepto, Comp Shopping, Trichotilo, Binge Eat, Paraphilias, IED
Affective-spectrum disorders:
IBS, migraines, fibromialg, chron pain, enuresis
sarhan

12. SSRIs Selective serotonin reuptake inhibitors
(citalopram- is an antidepressant drug prescribed for the treatment of major depression associated with mood disorders. Celexa is also used on occasion in the treatment of body dysmorphic disorder and anxiety.
Lexapro (escitalopram)- Lexapro is approved for the treatment of major depressive disorder and generalized anxiety disorder. Social anxiety disorder, panic disorder and obsessive-compulsive disorder are also some of the other indication for Lexapro.
Prozac (fluoxetine) – Prozac is prescribed to patients suffering from major depression (including pediatric depression), obsessive-compulsive disorder (in both adult and pediatric populations), bulimia nervosa, anorexia nervosa, panic disorder and premenstrual dysphoric disorder. It remains to this day one of the best-known antidepressant brands.
Zoloft (sertraline)- it has been approved for major depression, obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), panic disorder and social phobia (social anxiety disorder).
sarhan

13. SNRIs Norepinephrine Reuptake Inhibitors
Effextor (Venlafaxine)-is primarily used to treat major depression, generalized anxiety disorder, social anxiety disorder, and panic disorder in adults.
Cymbalta (duloxetine)-used to treat depression and generalized anxiety disorder. Duloxetine is also used to treat pain and tingling caused by diabetic neuropathy (damage to the nerves)and fibromyalgia. Its also used to treat ongoing bone or muscle pain such as lower back pain or osteoarthritis.
sarhan

14. Antidepressant half-lives (hrs)

15. Pharmacological Activity

16. Pharmacologic effects of antidepressants
Reduce depression
Psychomotor activation
Antiparkinsonian effects
Reduce depression
Reduce suicidal behavior
Antipsychotic effects
Hypotension
Ejaculatory dysfunction
Sedation
Sedation/drowsiness
Hypotension
Weight gain DA
reuptake
inhibition H1
block
5HT2
block
Blurred vision
Dry mouth
Constipation
Sinus tachycardia
Urinary retention
Cognitive dysfunction
Reduce depression
Antianxiety effects
GI disturbances
Sexual dysfunction
ACh block
Antidepressant
5HT reuptake
inhibition
Alpha2
block NE
reuptake
inhibition
Alpha1
block
Anxiety
Reduce depression
Antianxiety effects
Tremors
Tachycardia
Erectile/ejaculatory dysfunction
Postural hypotension
Dizziness
Reflex tachycardia
Memory dysfunction
Richelson. In: Current Psychiatric Therapy. 1997:

17. Indications of antidepressants
Depression
Social anxiety disorder
Panic disorder
OCD
PTSD
GAD
sarhan

18. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis

19. AUTHORS
Andrea Cipriani, Toshiaki A Furukawa, Georgia Salanti, John R Geddes, Julian P T Higgins, Rachel Churchill, Norio Watanabe, Atsuo Nakagawa,
Ichiro M Omori, Hugh McGuire, Michele Tansella, Corrado Barbui
Published online January 29, 2009 DOI: /S (09)
sarhan

20. Conclusion
Interpretation Clinically important differences exist between commonly prescribed antidepressants for both efficacy and acceptability in favour of escitalopram and sertraline
sarhan

21. Solotik -sertraline Depression OCD Panic disorder
Social anxiety disorder
GAD
sarhan

22. Purlex-escitalopram Depression GAD Social anxiety disorder.
Panic disorder
sarhan

23. Normal Synapse

24. Serotonin

25. Synapse in depression
sarhan

26. SSRI increases serotonin
5HT1a
sarhan

27. Some receptors may upregulate
sarhan

28. SSRI effects 5HT1a Anxiety down, mood up 5HT2a Insomnia, sex problems
5HT2c Agitation
5HT3 Nausea

29. FDA categories of Antidepressants in Pregnancy
Medication
Pregnancy Category
Lactation Risk
Fluoxetine C
Safety Unknown
Paroxetine D
Safe
Sertraline
Citalopram
Escitalopram
Bupropion
Possibly Unsafe
Venlafaxine
Nortriptyline
Probably Safe
Amitriptyline
Mirtazapine
Trazodone
Paxil- OR 2.08 for congenital malformations – VSD – retrospective 3581
Swedish registry study – 4 % paxil major congenital anom vs 2 % with other AD
6.1 OR for PPH

30. SSRIs Most widely prescribed drugs for depression.
They have few side effects and seem to be rather safe. More rational prescribing and better patient compliance.
Adverse effects include: nausea, decreased libido, decrease sexual function.
Low threat for overdose. Suicide may be considered in severe depression.

31. SSRIs Mechanism of action: Current theory holds that:
Specific serotonin uptake inhibitors increase 5-HT by inhibiting reuptake.
Current theory holds that:
Enhanced stimulation or responsiveness of postsynaptic 5-HT1A receptors is particularly important in the action of antidepressants.

32. SSRIs Fluoxetine is the prototype.
Approximately 70% of depressed patients will respond to an SSRI therapy at the end of 6 weeks (4 to 6 weeks before effects are evident to patient).
T1/2 of 16 – 24 hrs. except for fluoxetine’s metabolite norfluoxetine (T1/2 = 8 days).
Fluoxetine and paroxetine inhibit liver enzymes, particularly P450-2D6.
Paroxetine and Sertraline have PK parameters similar to TCAs.

33. SSRIs Drug-drug interactions:
dangerous with other antidepressant drugs, MAOIs in particular.
”Serotonin Syndrome”:
hyperthermia, muscle rigidity, myoclonus, rapid changes in mental status and vital signs.
Thus it is important to wait up to 6 weeks after medication is stopped, before starting with another drug.

34. Comparative side effects of antidepressants
sarhan

35. Sexual side effects
SSRIs can cause various types of sexual dysfunction such as anorgasmia, erectile dysfunction, and diminished libido .

36. Heterocyclics Mechanism of Action: 1) NT reuptake inhibition.
maprotiline.
2) 5-HT receptor antagonism (for 5-HT2A or 2C receptors).
nefazodone, mirtazapine, and trazodone
3) Alteration of NE Output.
bupropion, amoxapine, and trazodone.

37. Heterocyclics Third Generation
Mirtazapine. A derivative of mianserin. Antagonist of 5-HT2A or 5-HT2C receptors. Also antagonizes 2-adrenergic receptors, thus increasing NE and 5-HT release. Very sedating. Venlafaxine. Short plasma half-live, thus needs to be given in divided doses. Potent inhibitor of 5-HT uptake and weaker at NE reuptake (at low concentrations it acts like an SSRI).

38. Noradrenergic Control of Serotonergic Release
Receptors NE
2-AR
5-HT
1-AR
5-HT1
5-HT2
5-HT3 NE 1 2 3
Mianserin

39. Depression Aetiology and Treatment
Remission
Recovery
Relapse
Recurrence
Normalcy * *
Relapse
Symptoms
Progression
to disorder
Response
Severity
Syndrome
Acute
(6–12 weeks)
Continuation
(4–9 months)
Maintenance
(1 or more years)
Treatment phases
Time
Kupfer, 1991 8

40. Low Potential for Drug Interactions
Carbamazepine
Chlorpromazine
Ethinyloestradiol
Alprazolam
Amiodarone
Astemizole
Theophylline
Diazepam
Omeprazole
Diclofenac
Risperidone
Thioridazine
Diltiazem
Ibuprofen
Nifedipine
Verapamil
Codeine
Warfarin x x x x x x x x x
fluoxetine (ProzacTM) x x x x x x x x x x x
fluvoxamine (LuvoxTM)
citalopram (CipramilTM) x x x x
paroxetine (AropaxTM) x x x x x x x x
nefazodone (SerzoneTM)
sertraline (ZoloftTM) ? ? ?
Slide 35 - Low Potential for Drug Interactions
venlafaxine (Efexor®-XR)
Possible drug interactions based on inhibition of cytochrome P450systems1,2,3,4
In vitro* and in vivo# data indicates that Efexor is a weak inhibitor of CYP2D6*# and has minimal effects on CYP2C9*, CYP1A2*# and CYP3A4.*# Pharmacokinetic studies have also demonstrated no significant interaction with ethanol (CYP2E1) and diazepam (CYP2C19).5,6,7 • Product information for individual drugs should be consulted. • The absence of a drug from the lists does not imply lack of inhibition of these isoenzymes, or a different metabolic pathway. Evidence may be equivocal, or unavailable. ™ Trademarks: Aropax of Smith Kline Beecham, Prozac of Eli Lilly, Luvox of Solvay, Serzone of Bristol–Myers Squibb, Zoloft of Pfizer and Cipramil of Lundbeck. 5
References: 1. Nemeroff CB et al Riesenman C Richelson E Brøsen K 1996
5. Ereshefsky L Efexor Product Information Tatro DS 1995

41. Duration of antidepressant therapy summary
40% of people may relapse after an index depressive episode within 2 years, and 60% within 5 years
First episode:
Six months after recovery at same dose minimises risk of relapse
(n=839, RCT, one-year, Reimherr et al, Am J Psych 1998, 155,
Second episode:
1-2 years
Third or subsequent episode:
3-5 years or longer
(Frank and Kupfer, Arch Gen Psych 1990 and 1992)
sarhan

42. Tolerability & Safety
Superior 6 Months Retention Rates vs.Escitalopran , Sertraline, Citalopram, Paroxetine, Paroxetine CR, Bupropion, Mirtazapine, Mirtazapine OD
References
Brogan Inc. Prescription Tracking Report: SSRI Retention, November

43. Discontinuing or switching antidepressants
Why discontinue or switch antidepressants?
Lack of efficacy
Adverse effects
Patient discontinues of own accord
End of maintenance phase
sarhan

44. Discontinuation phenomena
Characteristics:
Commence within 1-3 days of stopping or reducing doses
Usually short-lived (1-2 weeks)
Rapidly suppressed by re-introduction of drug
Distinct from relapse or recurrence, which occur 2+ weeks after discontinuation
Can occur even with missed doses
sarhan

45. Discontinuation symptoms
Tricyclics:
Cholinergic rebound
headache, restlessness, diarrhoea, nausea
‘flu-like symptoms, cramps
lethargy
sleep disturbances
movement disorders
SNRI (venlafaxine):
Fatigue, headache, restlessness, nausea
abdominal distension, congested sinuses
“SSRI discontinuation”:
Dizziness, light-headedness
Sleep disturbances
agitation, volatility
electric shocks in the head
nausea, fatigue, headache
‘flu-like symptoms
Mirtazapine & reboxetine:
Little or nothing reported
MAOIs:
Confusion, delirium, psychosis
sarhan

46. Vagus Nerve Stimulation
For long-term therapy of treatment-resistant depression (TRD)
When at least four antidepressant drugs have failed
Mechanism of action
An implanted device
Delivers electrical pulses to the vagus nerve
Side effects
Hoarseness
Voice alteration
Cough
Dyspnea 46

47. Electroconvulsive Therapy
Outside the realm of pharmacology
Valuable treatment for depression
Two desirable characteristics
Effectiveness
Rapid onset (relative to antidepressant drugs)
Two primary types of patients
Those who have failed to respond to drugs
Severely depressed, suicidal patients
Can terminate ongoing depressive episode
Adverse effect
Some loss of memory for events immediately surrounding treatment 47

48. Alternative Therapies
No way of a priori knowing which therapy will be best for a patient.
Light Therapy
Psychological Treatment
ECT
Transcranial magnetic stimulation

49. Incidence Of Depression : 2000 Patients
100 - major
100 - minor
200 - subclinical
Depression. In 50% of patients it may not be acknowledged.

50. Anxiety Usually worth trying a antidepressant.
May be useful to avoid the stimulant ones !
May need higher doses.
Initiation may lead to paradoxical increase in symptoms. ? Cover with short course of anxiolytic.

51. Anxiety ? Role of benzodiazepines. ? Beta-blockers. Buspirone.
Some efficacy, but small.
Slow onset, 2-4 weeks.

52. Suicidality risk vs placebo (ideation or worse) in adults
Suicide risk (BMJ)
Suicidality risk vs placebo (ideation or worse) in adults
Drug n %
Placebo
Odds ratio
Escitalopram 10
3130
0.32% 5
2604
0.19%
2.44
Citalopram 24
2661
0.90% 7
1371
0.51%
2.11
Fluvoxamine 22
2187
1.01% 13
1828
0.71%
1.25
Mirtazapine 8
1016
0.79% 6
644
0.93%
0.97
Paroxetine 50
9919
0.50% 29
6972
0.42%
0.93
Duloxetine 25
2327
1.07% 18
1460
1.23%
0.88
Venlafaxine
5593
0.52% 30
3904
0.77%
0.71
Fluoxetine 81
7180
1.13% 67
4814
1.39%
Sertraline
6363
0.28% 28
5081
0.55%
0.51
All drugs
314
50043
0.63%
197
27164
0.73%
0.83
One might expect suicide risk rates on placebos to be the same.

53. Sexual Side-effects Total Desire Arousal Orgasm Severe Sertraline 27
Citalopram 55 82
Clomipramine 42
Venlafaxine 25
Paroxetine 47 54 18 20
Fluoxetine 46 44 16 17 43 39 15 23 31 14
Mild
Duloxetine 4
Fluvoxamine 6 11 12
Escitalopram 3
Mirtazapine 7 5 2
Moclobemide
Nil
Placebo 1
0.2
0.7
0.4
Treatment-Emergent Sexual Dysfunction Related to Antidepressants: A Meta-Analysis Serretti, Alessandro MD, PhD; Chiesa, Alberto MD. Journal of Clinical Psychopharmacology: June Volume 29 - Issue 3 - pp Abstract
This table shows the relative size of sexual side-effects of many antidepressants. The number is the Odds Ratio (OR) compared to placebo, such that placebo is defined as 1. The numbers are rounded to a whole number. Data from the Supplementary Table from the paper above.

54. S-(+)-citalopram (Escitalopram)
R-(-)-citalopram
50/50 mixture of both = Citalopram

55. Depression Most common psychiatric disorder
30% of the U.S. population will experience some form during their lifetime
Incidence in women 2x as high as in men
Risk of suicide is high in depression
Often untreated 55

56. Clinical Features Depressed mood Loss of pleasure or interest
Insomnia (or sometimes hypersomnia)
Anorexia (or sometimes hyperphagia)
Mental slowing and loss of concentration
Feelings of guilt, worthlessness, helplessness
Thoughts of death and suicide
Overt suicidal behavior
Symptoms must be present most of the day, nearly every day, for at least 2 weeks 56

57. Suicide Risk with Antidepressants
May increase suicidal tendency early in the treatment
Patients should be observed closely for:
Suicidality
Worsening mood
Changes in behavior
Precautions
Prescriptions should be written for the smallest number of doses consistent with good patient management
Dosing of inpatients should be directly observed 57

58. Conclusion Antidepressants are effective and safe
Antidepressants are used for a variety of conditions: depression and anxiety disorders
All physicians deal with antidepressants
sarhan

59. THANK YOU
sarhan