2. ORGANISATION
• NEUROBIOLOGY OF DEPRESSION
• GENETICS OF DEPRESSION
• RESPONSE, REMISSION, RECOVERY, RELAPSE AND RECURRENCE
• INDICATIONS OF AD
• MODE OF ACTION OF AD
• CLASSIFICATION OF AD
• ADJUNCTIVETREATMENTS
• HOW LONGTOTREAT?
• REFERENCES
3. NEUROBIOLOGY OF DEPRESSION
• Amine hypothesis: Depression is associated with decreased
amine-dependent synaptic transmission.
• Several brain circuits have also become dysfunctional.
• Almost all antidepressants affect metabolism or reuptake of
serotonin, norepinephrine, or both.
• Some are also selective antagonists of serotonin or
norepinephrine.
• The full clinical effects of drugs requires 4-8 weeks.
4.
5. NEUROBIOLOGY OF DEPRESSION
Unipolar depression
I. Emotional processing
Increased amygdala activation to negative scenes, fearful faces
Decreased or nil amygdala activation to happy faces
Decreased VmPFC activity during sad mood.
II. Executive control
Decreased DLPFC activity during memory and attention tasks
III. Emotional regulation
Impaired top down processing.
12. Mode of Action of ADs
All antidepressants function by increasing availability of
monoamines (5-HT, NA or DA) by one of the following methods:
• Presynaptic inhibition of reuptake of 5-HT, NA or DA.
• Antagonist activity at presynaptic inhibitory 5HT or NA receptors
which enhances neurotransmitter release.
• Inhibition of Monoaminase oxidase, reducing NT breakdown.
• Increasing availability of NT precursors.
Initial resolution of depressive symptoms takes minimum of 2-4 weeks.
22. • Off-label uses of SSRIs are follows -
• The antiorgasmic effects of SSRIs make them useful as a treatment for men with
premature ejaculation. SSRIs permit intercourse for significantly longer –
fluoxetine and sertraline
• SSRIs diminish the average time per day spent in unconventional sexual fantasies,
urges, and activities
• Sertraline and fluvoxamine have been shown in controlled and open-label trials to
mitigate aggressiveness, self-injurious behavior, repetitive behaviors, some degree
of language delay, and, rarely, lack of social relatedness in adults with autistic
spectrum disorders.
• Fluoxetine has been reported to be effective for features of autism in children,
adolescents, and adults.
23. • Concurrent administration of an SSRI with an MAOI, L-tryptophan, or
lithium can raise plasma serotonin concentrations to toxic levels, producing
a constellation of symptoms called the serotonin syndrome
• This serious and possibly fatal syndrome of serotonin overstimulation is
composed, in order of appearance as the condition worsens, of (1) diarrhea;
(2) restlessness; (3) extreme agitation, hyperreflexia, and autonomic
instability with possible rapid fluctuations in vital signs; (4) myoclonus,
seizures, hyperthermia, uncontrollable shivering, and rigidity; and (5)
delirium, coma, status epilepticus, cardiovascular collapse, and death.
24. Side-effects
• GI discomfort/ nausea
• Sexual dysfunction
• Sleep disturbance
• Dry mouth
• Tremor
• Headache
• Anxiety/ restlessness.
• Fatigue
Caution:
• Be aware of interactions-inhibitory
effects on P450 & changes with
alcohol, anticoagulants, MAOIs,
TCA, smoking etc.
31. • The treatment of a major depressive episode and the prophylactic
treatment of major depressive disorder are the principal indications for
usingTCAs
• Imipramine is theTCA most studied for panic disorder with agoraphobia
• Doxepin – GAD
• OCD appears to respond specifically to clomipramine, as well as the SSRIs
• Amitriptyline is theTCA most often used in pain syndromes
• Clomipramine - Premature ejaculation, movement disorders, and
compulsive behavior in children with autistic disorders
32. Side-effects
• Dry mouth,
• Blurred vision,
• Sedation,
• Orthostatic hypotension,
• Constipation,
• urinary incontinence.
• Disorientation or confusion
Caution:
• Arrhythmias & ECG changes. Monitor
Cardiac function, LFTs, UCEs.
• Should be used cautiously in elderly.
33. Overdose ofTCAs
• Are extremely dangerous in overdose (amoxapine and maprotiline
though not allTCA are as dangerous).
• More than 1 g of a tricyclic is potentially lethal
• TCAs increase suicidal risks.
• Manifestations are: mydriasis, respiratory depression, seizure, cardiac
arrhythmia and coma
34. TCA overdosage. Prolonged QRS interval and supraventricular
tachycardia with progressive widening of QRS complexes mimics
ventricular tachycardia.
35. SNRIs (Serotonin-norepinephrine reuptake inhibitors )
Mechanism: Similar to SSRI, Inhibit 5HT & NA (high doses DA)
• Venlafaxine (Effexor)
• Desvenlafaxine
• Duloxetine (Oxcym DR, Hapibar, Lyta)
• Levomilnacipran (Fetzima)
• Tramadol (Tramal, Ultram)
• Sibutramine (Meridia, Reductil)
Side-effects: Similar to SSRIs & may cause HTN.
36.
37.
38. • Venlafaxine has higher remission rates in depression than SSRIs by 6%
• The extended-release formulation of venlafaxine is approved for treatment of
GAD, SAD and panic disorder
• Venlafaxine may be beneficial in the treatment of OCD, agoraphobia, ADHD, and in
patients with a dual diagnosis of depression and cocaine dependence
• Duloxetine is formulated as a delayed-release capsule to reduce the risk of severe
nausea associated with the drug and used for depression, GAD, diabetic
neuropathy and stress urinary incontinence
• DVS - depression and for the alleviation of vasomotor symptoms (VMS) associated
with menopause
39. MAOIs (Monoamine oxidase inhibitors)
• Irreversible inhibition of
• MAO-A (acts on NA, DA, 5HT &Tyramine) &
• MAO-B (acts on DA,Tyramine,
Phenylethylamine, benzylamine) leading to
accumulation of monoamines in
Synaptic Cleft.
• RIMAs: Reversible inhibition of
MAO-A.
45. Tetracyclic antidepressants (TeCAs)
Mode: Similar toTCA without anticholinergic SE
Indications: TCA with sedation.
S/E- Cardiotoxicity
• Mirtazapine (Remeron) - NaSSA
• Mianserin (Bolvidon, Norval,Tolvon)
• Amoxapine (Asendin)
• Maprotiline (Ludiomil)
Noradrenergic and specific serotonergic antidepressant (NaSSA)
Mode: α2 inhibitor (^NA/5HT), 5HT1, 5HT2 antagonist.
Indications: Depression (+anxiety,wt loss) adjunct SSRI/venlafaxine to improve SxD, GI discomfort.
Advantages: LowToxicity, less sexual dysfunction & GI upset.
46.
47. • Mirtazapine (Remeron) is unique among drugs used to treat major
depression in that it increases both norepinephrine and serotonin through a
mechanism other than reuptake blockade
• Mirtazapine is effective for the treatment of depression.
• It is highly sedating, making it a reasonable choice for use in depressed
patients with severe or long-standing insomnia
• Mirtazapine is often combined with SSRIs or venlafaxine (Effexor) to
augment antidepressant response or counteract serotonergic side effects of
those drugs
MIRTAZAPINE
49. • Trazodone is structurally related to nefazodone (Serzone)
• The main indication for the use of trazodone is major depressive disorder
• Trazodone is a first-line agent for the treatment of insomnia because of
its marked sedative qualities and favorable effects on sleep architecture
• Trazodone is associated with an increased risk of priapism
TRAZODONE
50. • Structurally related to trazodone, not routinely used
• Used for treating major depression, panic disorder and panic with comorbid
depression or depressive symptoms, of generalized anxiety disorder, and of
premenstrual dysphoric disorder, and for the management of chronic pain
• increases sleep continuity
• Also of use in patients with PTSD and chronic fatigue syndrome
NEFAZODONE
52. • Bupropion is a monocyclic aminoketone
• A side-effect profile characterized by little risk of sexual dysfunction or
sedation, and with modest weight loss during acute and long-term
treatmentComparable to SSRIs in treating depression, even though SSRI
are first line
• Bupropion - prevents seasonal major depressive episodes in patients with a
history of SAD
BUPROPION
55. MELATONIN AGONISTS
• Ramelteon essentially mimics melatonin's sleep-promoting properties. It has high
affinity for melatonin MT1 and MT2 receptors in the brain
• Ramelteon mainly shortens latency to sleep onset and, to a lesser extent, increases
total duration of sleep.
• Melatonin (N-acetyl-5 methoxytryptamine) is a hormone mainly produced at night
in the pineal gland. Its secretion is stimulated by the dark and inhibited by light
• It is hypothesized that the antidepressant-like activity of Agomelatine most
probably involves a combination of both its melatonin agonist and 5-HT2C
receptor antagonist properties
57. • SSRIs are not sedative, safe in overdose and have mild adverse
effects so they are widely prescribed.
• Finding the right drug and the right dose must be accomplished
empirically.
• If it is the first depressive episode and if the treatment was
satisfactory, withdraw treatment after 6-9 months.
• A patient who has had previous episodes of depression is a
candidate for maintenance therapy.
• The duration of maintenance treatment varies and may
continue indefinitely.