DRUG THERAPY OF DEPRESSION

DRUG THERAPY OF DEPRESSION

• Depression: is a medical condition that is
characterized by a low mood and sleep
disturbances that occur persistently

• Bipolar depression: formerly known as manic

depression disease, refers to patients who
present with mixed episodes of both mania
and depression
 ETIOLOGY

• Genetic predisposition
• Environmental factors: stress events
• Biochemical factors
• Medication
• Other illness
 Epidemiology
• Average age of onset –late 20
• It affects 3-10% of the population.
• With the incidence increasing in age and it is
more common in females
• s
 Pathophysiology of Depression
• Changes in brain monoamine
neurotransmitters occur resulting in a
reduction or functional deficiency of
noradrenaline and serotonin
 Medications that may Cause or
Exacerbate Depression

• Cardiovascular agent: beta-blockers, clonidine,

methyl dopa
• CNS agents: alcohol, zolpidem,
benzodiazepines
• Hormonal agents: corticosteroids, oestrogen
• Others: isotretinoin
 DIAGNOSIS
• Diagnosis of depression is usually based on
American Psychotic Association in addition to
present signs and symptoms
 DRUGS IN DEPRESSION
• Depression is characterized by misery, malaise,
despair, guilt, apathy, indecisiveness, low
energy and fatigue, changes in sleeping
pattern, loss of appetite and suicidal thoughts
 DRUGS IN DEPRESSION
• MONOAMINE THEORY OF DEPRESSION
• Postulate s that symptoms of depression are
caused by a functional deficiency of CNS: NA
and/or 5HT
• This is based on the observation that most
antidepressant affect the metabolism of these
amines. Again there are exceptions
 DRUGS IN DEPRESSION
• MONOAMINE THEORY OF DEPRESSION
• Reserpine depletesNE,5HT, and causes severe
depression
• Acute mechanism of antidepressants: increased NE,
increased 5HT
• However antidepressants effect takes several weeks to
occur
• Cocaine, amphetamine, L-dopa increase monoamine
have no effect on the mood of depressed patients
• 2 weeks to show effect
 DRUGS IN DEPRESSION
• MONOAMINE THEORY OF DEPRESSION
• It is unlikely, therefore, that monoamine
mechanisms alone are responsible for the
symptoms of depression
• Other systems may involved in depression
include: the GABA system, Neuropeptides
(vasopressin, endogenous opioids), secondary
messenger systems also appear to have crucial
role in some treatments
 DRUGS IN DEPRESSION
• Major classes of antidepressant drugs and
their mechanisms of action
1.Tricyclic antidepressants(TCAs): amitriptyline,
imipramine.
MOA: non-specific blockers of monoamine
uptake
Cautions: epilepsy, hepatic impairment, CVS
disease glaucoma, history of urinary retenstion
 DRUGS IN DEPRESSION
Major classes of antidepressant drugs and their
mechanisms of action

• 2. Selective serotonin reuptake

inhibitors(SSRIs): fluoxetine, praxetine sertraline
MOA: selective blockers of 5-HT reuptake
Cautions: epilepsy, diabetes, glaucoma, history of
bleeding
 Safety Issues and SSRIs
• Suicidal tendencies: use in patients under 18
years is not recommended

• Gastrointestinal bleeding: SSRIs inhit uptake

and therefore storage of serotonin of platelets.
This is significant because release of serotonin
from platelets augment their aggregation
 Safety Issues and SSRIs
• Relative risk of GI bleeding similar to use of
NSAIDs
• Avoid in elderly and in patients who are
concurrently using NSAIDs
• Consider the use of a proton-pump inhibitor in
high risk patients
 DRUGS IN DEPRESSION
• Major classes of antidepressant drugs and
their mechanisms of action

• 3. Serotonin-noradrenaline reuptake
inhibitors(SNRIs): Venlafaxine

MOA: selective blockers of 5-HT and

noradrenaline uptake
• Side effects are very similar to those found
with SSRIs
 DRUGS IN DEPRESSION
• Tricyclic antidepressants: Therapeutic uses
• Depression: there is a delay of about 2 weeks
before benefit is seen. Amtriptyline is sedative,
and this can be a useful property
• Other tricyclics can be chosen that lack this
sedative effect
• Chronic pain: TCAs are also used for the
treatment of neuralgia
 DRUGS IN DEPRESSION
• Tricyclic antidepressants: adverse effects

• TCAs are antagonists of muscarinic, histamine

H1receptors and alpha 1 adrenoceptors:
anticholinergic effect include urinary retention,
constipation and tachyarrhythmias
• Cardiac arrhythmia may also occur because of
effects on intracardiac conduction
 DRUGS IN DEPRESSION
• Tricyclic antidepressants: adverse effects

• Sedation is particularly problem with

amitriptyline
• Weight gain can occur
• Exacerbation of epilepsy
 DRUGS IN DEPRESSION
• Drug interactions

• Additive with CNS depressants

• TCAs should be combined with MAOIs
 DRUGS IN DEPRESSION
• Selective serotonin reuptake inhibitors(SSRIs)
• Fluoxetine: (Prozac): is well absorbed from the
gut and is metabolised to an equipotent
metabolite.
• Both parenet drug and active metabolite are
very slowly eliminated and may accumulate in
severe liver or kidney disease
 DRUGS IN DEPRESSION
• Selective serotonin reuptake inhibitors(SSRIs)
• Sertaline: in contrast has a shorter elimination
half-life and is metabolised to inactive
derivative
• Others: citalopram, paroxetine
 DRUGS IN DEPRESSION
• Selective serotonin reuptake inhibitors(SSRIs)
• Therapeutic notes on SSRIs: unlike TACs,SSRIs
do not have marked sedative, hypotensive or
anticholinergic effects and have less effect
cardiac conduction
• In overdose, the SSRIs are better tolerated
than TCAs
 DRUGS IN DEPRESSION
• Adverse effects and contraindications of SSRIs:
• Suicidal behaviour is a recognised risk in
people under 18 years and the SSRIs should
not be used in this group
• Seizure, anorexia, sexual dysfunction, weight
loss
• SSRIs can cause hyponatremia
 DRUGS IN DEPRESSION
• Drug interactions:

• avoid the combination of fluoxetine

with lithium ( increase the risk of seizure)
 DRUGS IN DEPRESSION
• Venlafaxine: is reserved for resistant cases of
depression. It is containdicated in severe
hepatic and renal diseases
• High doses may cause hypertension
 DRUGS IN DEPRESSION
• Major classes of antidepressant drugs and
their mechanisms of action
4.Monoamine oxidase inhibitors(MAOs):
There are two subtypes of MAO: MAO-A
metabolises NA and 5HT and therefore
relevant to depression

MAO-B metabolises dopamine

 DRUGS IN DEPRESSION
• 4.Monoamine oxidase inhibitors(MAOs)
• Moclobemide: is a reversible inhibitor of MAO-A .
It is well absorbed from the gut and cleared by
hepatic metabolism; its half-life is short and
therefore is given twice daily
• Unlike older MAOIs moclobemide does not carry a
high risk of hypertensive crises with
sympathomimetics , but patient should avoid
heavy intake of tyramine-rich food
 DRUGS IN DEPRESSION
• St.john’s wort is a popular herbal treatment for
mild depression and seems to produce benefit
• St.john’s wort is a hepatic enzyme inducer, and
interacts with a wide variety of therapeutic
drugs
 DRUGS IN DEPRESSION
• Clinical sketch

• A 40-year-old woman has been depressed

since the death of her husband 6 months ago.
She has lost 9 kg in weight and is unable to
work. The doctor starts her on amitriptyline
but there is no improvement for two months
 DRUGS IN DEPRESSION
• Comment on the clinical sketch: sadness is a
normal reaction to many life events. Usually
this abates with time but the term depression
is used for abnormally protracted or severe
sadness. It is common and if ignored, may
result in anorexia , retardation, somatic
symptoms and disruption of normal life.
Suicide may be attempted and suicidal ideas
 DRUGS IN DEPRESSION
• Comment on the clinical sketch cont’d: should
be asked about when assessing such patients.
Choice of antidepressant drug can be difficult
and is usually empirical; trials show them to be
equipotent and improvement in mood can take
several weeks with all agents. The SSRIs(e.g.
fluoxetine) are safer than TCAs after overdose