Depression: is the most common of
affective disorders; disorder of mood
rather than disturbances of thought or
cognition. it may range from a very mild
condition, bordering on normality, to
severe (psychotic) depression accompanied
by hallucinations and delusions.
The symptom of depression include emotional & biological:
intense feeling of sadness, hopelessness and despair
inability to experience pleasure in usual activities,
Low self-esteem: feelings of guilt, inadequacy and ugliness
Indecisiveness, loss of energy and motivation, and suicidal thoughts.
Retardation of thought and action
Loss of libido
changes in sleep patterns and appetite,
Mania is characterized by the
opposite behavior that is
rapid thought and speech
Major types of depression
The three major types of depression are:
1. Reactive depression, a response to external event:
adverse life events, grief, physical illness, and drugs (reserpine).
2. Bipolar affective (manic-depressive) disorder:
flight of ideas,
and poverty of sleep.
3. Major depressive disorder (unipolar 75%, endogenous depression 25%):
a depression of mood without any obvious medical or situational causes,
3. Major depressive disorder
• inability to cope with ordinary events or
• anorexia, with significant weight loss,
• insomnia, fatigue, and inability to
Depression is due to deficiency in neuronal and synaptic
catecholamine concentration, such as NE and 5-HT at certain key
sites in the brain.
Mania: excess amines
Biologic Amine Hypothesis
This theory was based on observations that:
Most clinically useful antidepressant drugs
potentiate, either directly or indirectly, the
actions of norepinephrine (NE) and/or
serotonin (5-HT) in the brain.
Reserpine (which was used to Rx
schizophrenia and HTN) caused sever
depression in ~15% of patients. This drug
depletes neuronal stores of monoamines.
Iproniazide (MAOI) used to treat TB
sometimes induced euphoria.
Mechanism of action
Although antidepressant drugs may
cause changes in brain amine
activity within hours, weeks
may be required for them to
achieve clinical effects!!!!
Q. What is happen in depression?
The monoamine in the limbic
system are depleted →
upregulation of postsynaptic β
receptor & presynaptic α2, 5-HT2A,
Q. What is antidepressant
Antidepressant drug decrease the
presynaptic inhibitory receptor densities in
the brain over a two-to four-week period
upregulation → downregulation → greater
synthesis and release of neurotransmitters
into the synaptic cleft → enhanced
signalling in the postsynaptic neurons,
presumably leading to therapeutic
• a group of chemically unique drugs
• They specifically inhibit serotonin reuptake,
• They have 300 to 3000 fold greater selectivity for the
serotonin transporter as compared to the NE transporter.
• They typically take 2 to 12 weeks to produce improvement in
• SSRI have little ability to block the dopamine transporter.
• SSRI have little blocking activity at muscarinic, α-adrenergic,
and histaminic H1 receptors (fewer side effects).
Thus, they are well tolerated by patients with heart disease, the elderly, who are
especially sensitive to the anticholinergic and orthostatic effects of the TCA.
Therapeutic uses of SSRIs:
Obsessive compulsive disorder (the only indication
for fluvoxamine ).
Panic disorder .
Generalized anxiety .
Premenstrual dysphoric disorder .
Bulimia nervosa (only fluoxetine is approved for this last
• All the SSRIs are well absorbed after oral administration,
• Only sertraline undergoes significant first-pass metabolism.
• Fluoxetine (Prozac) and Sertraline (Zoloft) are given in the morning
because of its potential for being activating and causing insomnia.
• The majority of SSRIs have plasma half-lives that range between 16 and 36
• Metabolism by P450-dependent enzymes and glucuronide or sulphate
conjugation occur extensively.
• Excretion of SSRIs is primarily through the kidneys, except for paroxetine
and sertraline, which also undergo faecal excretion.
Fluoxetine differs from the other members of the class in two respects :
It has a much longer half-life (50hrs).
The metabolite is as potent as the parent compound . the half-life of the
metabolite is quite long, ~10 days.
Fluoxetine and paroxetine are potent inhibitors of a hepatic CYP P450
CYP2D6 responsible for the elimination of TCA drugs, neuroleptic drugs, and
some antiarrhythmic and β-adrenergic antagonist drugs.
Note; about 7% of the white population lack (CYP2D6) and, therefore
matabolize fluoxetine very slowly.
• With initiation of therapy with an SSRI, some patients describe
anxiety or agitation. Insomnia
• Paroxetine and fluvoxamine are sedating, and may be useful in
patients who have difficulty sleeping.
• Conversely, patients who are fatigued may benefit from one of
the more activating antidepressants, such as fluoxetine.
• Sexual dysfunction: loss of libido, delayed ejaculation, and
Replace with a drug having fewer sexual side effects, such as
Bupropion or mirtazapine.
• The SSRIs tend to be weight neutral with the exception of
paroxetine (Paxil), which is associated with weight gain.
• Use in children and teenagers: 1/50 children become more
suicidal as a result of SSRIs treatment.
• SSRI+MAOIs cause Serotonin syndrome: characterized by:
hyperthermia, muscle rigidity, myoclonus and changes in mental status and
Venlafaxine and duloxetine, selectively
inhibit the reuptake of both serotonin
effective in treating depression and
neuropathic pain (such as backache and
muscle aches) in patients in which SSRIs
SNRIs, unlike the TCAs, have no activity at
adrenergic, muscarinic, or histamine
receptors and thus have fewer side
effects than the TCAs.
Venlafaxine vs Duloxetine
• Is a potent inhibitor of serotonin
inhibits serotonin and NE
reuptake and, at higher doses, is an
reuptake at all doses.
inhibitor of NE reuptake. It is also a
mild inhibitor of dopamine reuptake. It is extensively metabolized in
the liver to numerous
• It has minimal inhibition of the CYP
metabolites, should not be
P450 isoenzymes. The t1/2 of the
administered to patients with
parent compounds plus its active
hepatic insufficiency. Metabolites
metabolite is approximately 11
are excreted in the urine.
Food delays the absorption of the
• SE: nausea, dizziness, insomnia,
drug. t1/2 is ~12 hours.
sedation, and constipation. At high
SE: nausea, dry mouth, and
doses, there may be an increase in
constipation are common,
Insomnia, dizziness, somnolence,
sweating, Sexual dysfunction also
They are a mixed group of agents that have actions at several different sites.
Bupropion: (smoking cessation)
• Acts at unidentified site. It has minimal effects on NE or 5-HT systems, but
blocks DA reuptake.
• Its short half-life may require more than once-a-day dosing or the
administration of an extended release formulation, it decreases the craving
of nicotine in tobacco abusers.
• Side effects include: dry mouth ,sweating ,tremor and seizures at high
• block 5-HT2 and α2 receptors.
• It is a sedative because of its potent antihistaminic activity, which may be
used to advantage in depressed patients having difficulty sleeping,
• but it does not cause the antimuscarinic SEs of TCAs,
• Does not interfere with sexual functioning, as do the SSRIs.
• Increased appetite and weight gain frequently occur.
Nefazodone and trazodone:
• Nefazodone (P450 inhibitor) blocks both NE and 5-HT reuptake, and
is a 5-HT2 antagonist,
• trazodone weak inhibitor of serotonin reuptake by blocking 5-HT1
presynaptic autoreceptors and thereby, increase serotonin release,
and is a 5-HT2 antagonist.
• Both are sedating because of potent H1 blocking activity.
• Trazodone has been associated with causing priapism.
• Tertiary amines; imipramine (prototype), amitriptyline, clomipramine,
doxepin and trimipramine
• Secondary amines; desipramine, and nortryptyline (N-demethylated
metabolites of imipramine and amitriptyline respectively), amoxapine,
maprotiline, and protriptyline.
Mechanism of Action:
Inhibition of neurotransmitter (serotonin and NE) uptake: ↑adrenergic
and serotonergic neurotransmission.
Blocking of four receptors: serotonergic, α-adrenergic, histaminic, and
actions at these receptors are probably responsible for many of the
untoward effects of TCAs.
Mechanism of action:
• Sever major depression,
• phobic and panic anxiety disorders,
• Neuropathic pain,
• obsessive compulsive disorder (OCD),
• nocturnal enuresis; Imipramine has
been used to control bed-wetting in
children (older than six years) by
causing contraction of the internal
sphincter of the bladder.
Muscarinic blockade leads to blurred vision, xerostomia,
urinary retention, constipation, and aggravation of
glaucoma and epilepsy.
Sympathomimetic: in tremor, and cardiac overstimulation,
α-adrenergic receptors blockade, causing orthostatic
hypotension and reflex tachycardia.
Imipramine is most likely and nortriptyline is least likely to cause
H1 receptors blockade; Sedation
Metabolic: Weight gain is a common adverse effect of the
Endocrine: Sexual dysfunction, as evidenced by erectile
dysfunction in men and anorgasmia in women.
Hyperthermia, seizures, coma, and death with MAOIs,
serotonin syndrome with SSRIs,
Mechanism of action: They increase stores of norepinephrine
,serotonin and dopamine within the neuron and subsequent
diffusion of excess neurotransmitter into the synaptic space.
Indicated for depressed patients who are unresponsive
or allergic to TCAs.
Patient with low psychomotor activity.
Treatment of phobic states .
These drugs inhibit not only MAO in the brain but also
peripheral oxidase, therefore MAOIs show a high incidence of
drug-drug and drug-food interactions.
• Cheese reaction: Individuals receiving MAOIs are unable to
degrade tyramine obtained from the diet, tyramine causes
the release of large amounts of stored catecholamine from
nerve terminals, resulting in headache, tachycardia, nausea,
hypertension ,cardiac arrhythmias and stroke .
• Other side effects include: drowsiness, orthostatic
hypotension ,blurred vision, dry mouth, dysuria and
Treatment of mania and bipolar
• For more than 40 years, Lithium (Li+) has been used to
• lithium carbonate is effective in 60 to 80% of all acute
manic episodes within 5 to 21 days of beginning
• Because of its delayed onset of action in the manic
patient, Li+ is often used in conjunction with low doses
of high-potency anxiolytics (e.g., lorazepam) and
antipsychotics (e.g., haloperidol) to stabilize the
behaviour of the patient..
Mechanism of Action:
Lithium interferes with the resynthesis (recycling) of PIP2,
by inhibition of the dephosphorylation of both IP2 to IP,
and IP to Inositol, necessary steps in the recycling of
inositol→↓ PIP2 in neuronal membranes of the CNS.
Lithium, Mechanism of Action
• Lithium is given orally, and the ion is excreted by the kidney like Na+;
• low Na+ diet or chronic diuretic treatment enhances toxicity, medical
conditions (diarrhoea), or physical activities (those that induce sweating)
that deplete the body of Na+.
• Lithium salts are very toxic. Their safety factor and therapeutic index are
extremely low-comparable to those of digitalis.
• ataxia, tremors, confusion, convulsions, acne, edema, visual dysfunction,
• goiter, hypothyroidism; nephrogenic diabetes insipidus (treat with
amiloride, not thiazides), teratogenicity (cardiac malformations, neonatal
cyanosis, and hepatomegaly);
Other Mood-Stabilizing Agents
• Several anticonvulsant; Valproic acid and carbamazepine are the best
studied to date.
• In 1995, valproic acid was approved by the FDA for treatment of acute
mania and is now considered a first-line agent.
• In pregnancy clonazepam or gabapentin are preferred.
• Other anticonvulsants under investigation include lamotrigine and
• The atypical antipsychotics (risperidone, olanzapine, ziprasidone,
aripiprazole, asenapine, and quetiapine) have also received FDA
approval for use in acute mania and mixed episodes associated with