Depression

Monoamines in depression

Serotonin
Noradrenaline
Dopamine

Antidepressants, I

Tricyclic antidepressants (TCA)

Selective serotonin reuptake inhibitors (SSRI)
Monoamine oxidase inhibitors (MAOI)
Noradrenaline and dopamine reuptake inhibitors (NDRI)
Selective noradrenaline uptake inhibitors (SNRI)

Antidepressants, II

Serotonin and noradrenergic reuptake inhibitors (SSNRI)

Noradrenaline and specific serotoninergic antidepressant (NaSSA)
Serotonin 2A antagonist/reuptake inhibitor (SARI)
Monoamine in depression

Serotonin

Deficiency causes depressed mood, anxiety, panic, phobia, anxiety, obsession, compulsion, food
craving and bulimia.

Serotonin is synthesized from tryptophan:

Serotoninergic neurons are concentrated in the Raphe nucleus in the brainstem. It projects to
frontal cortex for mediation of mood; projection to basal ganglia mediates akathisia, agitation,
obsession and compulsions, to the limbic system for anxiety, hypothalamus for appetite, sleep
centers for insomnia spinal cord for sexual function and vomiting center for nausea and vomiting.

Serotoninergic neuron also exist in the gut, when overstimulated causes GI cramps and diarrhea.

Noradrenaline

Deficiency causes impaired attention, problem with concentration, working memory, slowness of
information processing, depressed mood, psychomotor retardation and fatigue.

Noradrenaline is synthesized from tyrosine:

Noradrenaline neuron are concentrated in an area called ‘locus coeruleus’. It projects to frontal
lobe, mediating mood and attention, to limbic system mediating energy/fatigue and psychomotor
agitation/retardation, to cerebellum mediating motor movements (tremor), brainstem (blood
pressure) and works on heart and bladder (tachycardia and urinary retention).
Dopamine

There are four pathways in the brain using dopamine as the major neurotransmitter:

- Mesocortical (cognition; negative sx in schizophrenia)

– ventral tegmentum  cortex
- Mesolimbic (positive symptoms in schizophrenia)
– ventral tegmentum  nucleus accumbens
- Nigrostriatal (EPS in patients treated with antipsychotics)
– substantia nigra  striatum
- Tuberoinfundibular (prolactin production)
– arcuate nucleus  hypothalamus

Dopamine is synthesized in the same pathway as noradrenaline:

There are 5 receptors for dopamine, from D1-D5. D2 receptor is stimulated by dopaminergic
agonist for the treatment of Parkinson’s disease and blocked by dopamine antagonist neuroleptics
and atypical antipsychotics for treatment of schizophrenia.
Tricyclic antidepressants
Amitriptyline, Imipramine, Clomipramine, Nortriptyline

Pharmacokinetics
All tricyclics are rapidly absorbed and widely distributed. There are genetic variation in liver
metabolism – one in 20 caucasian has problem with P450 2D6 which make them poor
metabolisers of TCAs.

The half-life of TCAs (or their active metabolite) is in the order of 24-36 hours.

Actions
Most tricyclic antidepressants have FIVE different actions :-

- Serotonin reuptake inhibitor (more potent with tertiary amine)

- Noradrenergic reuptake inhibitor (more potent with secondary amine)
- Histamine H1 blocker
- Muscarinic blocker
- Alpha-1 adrengic blocker

Note that the initial two effects are responsible for the beneficial effect on depression, anxiety
disorders and eating disorders; (antidepressant and anxiolytic functions). Note that by blockade of
serotonin reuptake weight gain occur as a result of stimulation of 5HT-2 receptors.

The second action – by blocking histamine H1 receptor, this leads to anxiolytic action, sedation,
weight gain (improved appetite – put it in the other way) and drowsiness can be useful or bad
depending on situations.

The later two action (muscarinic blocking and alpha-1 adrenergic blocking effect) are responsible
for most of the side effects of the medication. Muscarinic blockade would result in symptoms such
as dry mouth, constipation, urinary retention, problem with visual accommodation as well as
glaucoma. Alpha-1 blockade would lead to postural hypotension and sedation.

Note that all tricyclic antidepressants are class I antiarrhythmic and can lead to heart block
(complete heart block, etc.) as well as prolongation of QT interval. They are thus contraindicated in
heart block as well as recurrent myocardial infarction.

Tricyclic antidepressants can also cause delirium, movement disorder and convulsion as their
neurotoxic effect.

Discontinuation syndrome occur when tricyclic is withdrawn. (See SSRIs)

Drug interactions
All tricyclics are metabolized by the enzyme system P450 2D6. P450 2D6 is inhibited by cimetidine
(histamine H2 receptor antagonist), paroxetine and fluoxetine (SSRIs) potently, secondary TCAs to
a moderate extent and other antidepressants (bupropion, venlafaxine, nefazodone and other
SSRIs); these increases TCA serum levels. Barbiturates induces P450 2D6 so decreases serum
levels of TCA by induction of enzymes.

Secondary TCAs are inhibitors of P450 2D6. Tertiary TCAs inhibit P450 1A2 and most tricyclics
inhibit P450 3A4. TCA thus potentiate warfarin action.

TCAs can be used to beneficial effect with lithium, SSRIs and L-tryptophan.
Selective serotonin reuptake inhibitors
Fluoxetine (Prozac®), Paroxetine(Seroxat®), Sertraline(Zoloft®), Fluvoxamine(Luvox®),
Citalopram(Cipram®)

Pharmacokinetics
SSRIs are rapidly absorbed and metabolized by liver. Fluoxetine has the longest halflife (200 hours
for its active metabolite) whereas drugs such as fluvoxamine has half life of 15 hours.

It has low concentration in breast milk (except fluoxetine).

Action
Serotonin reuptake inhibitors are thought to work by first increasing somatodentritic
concentration of serotonin, which causes a desensitization of 5HT-1A autoreceptor (i.e.
downregulation) which lead to both increase in serotonin secretion by the neuron as well as
reduction of side effects as the drug is used for some time.

Selective serotonin reuptake inhibitors are relatively selective in their action. All SSRIs have potent
SRI effect, as well as a range of other action such as:

- Noradrenergic reuptake inhibitor, 5HT-2c agonist, 2D6/3A4 inhibitor (fluoxetine)

- Sigma action, dopamine reuptake inhibitor (sertraline)
- Noradrenergic reuptake inhibitor, muscarinic antagonist, nitric oxide synthase inhibitor,
2D6 inhibitor (paroxetine)
- Sigma action, 1A2/3A4 inhibitor (fluvoxamine)

Citalopram/escitalopram (which is the S-enantiomer of citalopram) is relatively selective for

serotonin reuptake and do not demonstrate any appreciable effect in other receptors.

Side effects of SSRIs stems from the effect of serotonin excess – nausea, vomiting, agitation,
akathisia, insomnia and sexual dysfunction. Sedation and dizziness occasional occurs.
Parkinsonism and convulsion are rare but reported side effects. There is also controversy about the
increased risk of suicidality (associated with agitation/akathisia).

Serotonin syndrome is an acute toxic syndrome due to increased 5-HT activity, characterized by
confusion, myoclonic jerks and hyperreflexia, pyrexia, sweating and autonomic instability. There
are gastrointestinal symptoms and mood change (especially towards mania). In this case drug
should be stopped.

Manic chimps with GI discomfort – Confusion, Hyperreflexia, Instability of autonomic

system, Myoclonic jerks and Pyrexia, Sweating

SSRI discontinuation syndrome is characterized by sensory abnormality, disequilibrium, insomnia,

vivid dreams, general somatic symptoms, mood change and rarely, psychotic symptoms.

I, 3D and 3S – Insomnia, Disequilibrium, Dreams, Depression, Somatic symptoms, Sensory

abnormality and Schizophrenia (for psychotic symptoms)

Drug interactions

SSRIs interact with MAOIs and St. John’s Wort.

Fluvoxamine interacts with P450 1A2 – interacts with caffeine, clozapine and theophylline
Fluoxetine and paroxetine interacts with P450 2D6 and 3A4, interacts with antipsychotics, opiates,
tricyclic antidepressants, class Ic antiarrhythmics and beta blockers.
Monoamine oxidase inhibitors
Phenelzine, Tranylcypromine, Selegiline, Moclobemide (Aurorix®/Manerix®; RIMA)

Pharmacokinetics
MAOIs are rapidly absorbed. The only pharmacokinetic concern is that toxic levels can build up in
slow acetylators – the other pharmacokinetic parameters are not important because the time of
action is that of the time taken to replace stores of MAO (2 weeks) because except moclobemide all
other MAOIs are irreversible inhibitors.

Action
MAOIs irreversibly/reversibly (for moclobemide) binds to monoamine oxidase and inhibits their
action. It increases concentration of virtually all amines and exerts their effect.

There are two forms of MAO, MAO A, inhibition of which is linked to antidepressant (and
hypertensive) effect. MAO B, inhibition of which is linked to neuroprotection (e.g. in
parkinsonism). Inhibition of MAO B with MAO-B inhibitors has no antidepressant effect when
MAO-B inhibitors is used at doses that are selective for MAO-B.

MAOIs are third line agents for severe depression, atypical depression as well as anxiety disorders.

MAOIs causes postural hypotension, restlessness, insomnia, peripheral edema, nausea, dizziness,
sexual difficulties, sweating and tremor.

Drug interactions
MAOIs causes hypertensive reaction when the patient taking MAOIs are taking tyramine-
containing food such as cheese, yeast extracts, hung game, some alcoholic drinks, broad bean pods
and pickled herring, or when they take drugs containing sympathomimetic amines such as
phenylephrine.

The symptoms of hypertensive reaction are that of flushing, headache, increased blood pressure
and rarely cerebral hemorrhage.

MAOIs are contraindicated in patients with cardiovascular and cerebrovascular diseases, in

children, in epileptic patients, patients with hepatic disease, phaeochromocytoma or
hyperthyroidism.
Noradrenaline and Dopamine Reuptake Blockers
Bupropion (Zyban®)

Pharmacokinetics
Bupropion is metabolized in liver into its three active metabolites, hydroxybupropion (half-life 20
hours), theohydrobupropion (half-life 37 hours), erythronhydrobupropion (half-life 33 hours). The
active metabolites are further metabolized into inactive metabolites and are excreted in the urine.

Action
Bupropion has both noradrenaline and dopamine reuptake inhibitor effect, with a more potent
dopamine reuptake effect than noradrenaline reuptake effect. Bupropion is generally
activating/stimulating, and is not associated with bothersome sexual dysfunction that comes with
SSRIs because bupropion lacks significant serotonergic component in its mechanism of action.

It is useful in patients whose depression does not respond to boosting serotonin by SSRIs. It also
reduces craving associated with smoking cessation.

Side effects includes dry mouth, insomnia, anxiety, gastrointestinal disturbance, sweating and
hypertension. At higher dose (e.g. 600mg/day) it has a high propensity (2%) of causing seizures.
Lower dose (e.g. 300-450mg/day) the propensity is decreased (0.1-0.4%).

Bupropion is known to decrease seizure threshold and thus is contraindicated in patients with
epilepsy, anorexia nervosa or bulimia.

Drug interactions
Bupropion is primarily metabolized by P450 2B6 isoenzyme (NOT 2D6). Thus, bupropion
interferes with metabolism of thiotepa, cyclophosphamide and orphenadrine. (Note that P450 2B6
also metabolises nicotine)

Its inhibition effect with P450 2D6 also interferes with metabolism of TCA, phenothiazine type of
antipsychotics, Class Ic antiarrhythmics and beta blockers.

Selective noradrenergic reuptake inhibitors

Roboxetine

Action
Noradrenaline reuptake inhibitors are logical pharmacological complement to SSRIs, and are
useful for treatment of noradrenergic deficiency syndrome (sometimes called ‘apathetic response’
to SSRI).

Depression associated with fatigue, apathy and notable cognitive disturbance (concentration and
memory), are theoretically more responsive to NRIs than of other drugs;

Side effects of NRIs seem to involve noradrenaline effect on brain, spinal cord, heart, GI tract and
urinary bladder (insomnia, tremor, tachycardia, postural hypotension and urinary retention).
Serotonin and noradrenergic reuptake inhibitors (SNRI)
Venlafaxine (Effexor®), duloxetine(Cymbalta®), sibutramine(Reductil®), tramadol(Zydol®)

Action
Venlafaxine is a selective 5-HT and NA reuptake inhibitor, and has a small DA reuptake inhibition
effect seen only at higher doses.

Pharmacologic action – Dose

Serotonin reuptake inhibitor

150 mg
Serotonin and noradrenergic
reuptake inhibitor
300 mg
Serotonin, dopamine and
noradrenergic reuptake inhibitor

Venlafaxine has enhanced efficacy in severe depressive disorder; When dose exceeds 200 mg per
day blood pressure need to be monitored. Specialist supervision is required for initiation of
venlafaxine in patients requiring more than 300mg/day.

Venlafaxine is contraindicated in patients with high risk of severe ventricular arrhythmia and
uncontrolled hypertension.

Venlafaxine may cause significant discontinuation symptoms (I, 3D’s, 3S’s)

Duloxetine is also a 5-HT and NA reuptake inhibitor with weak inhibition of DA reuptake. It has
positive effect on painful physical symptoms in patients with depression. Use carefully in patients
with liver disease.

Duloxetine cannot be used with alcohol, and in alcoholic patients this drug may prove harmful.

Sibutramine is used for treatment for obesity.

Tramadol is a kappa (of opiate receptor) agonist with SNRI activity which is used for treatment of
pain.
Dual serotonin and noradrenaline action via alpha-2 antagonism
Mirtazapine

Action
Mirtazapine has several action which allows its function to be actuated:-

- alpha-2 antagonist
- histamine H1 antagonist
- 5HT-2A, 5HT-2c, 5HT-3 antagonist

It blocks alpha-2 autoreceptor in its presynaptic membrane of the noradrenergic neuron, causing
release of noradrenaline, which causes both direct effect on increase in noradrenaline level as well
as secondary activation of alpha-1 receptor on serotonin neuron. This causes increase in firing of
the serotoninergic neuron.

In addition, it blocks the post-synaptic alpha-2 heteroreceptor in the presynaptic terminal of the
serotoninergic neuron which causes release of more serotonin.

It also reduces the side effect of enhanced serotonin outflow by blocking 5-HT2A, 2c and 3
receptors which mediates sexual dysfunction, gastrointestinal and nausea problems.

Its histamine-H1 antagonist action contribute to increased appetite and sedation. This sedation is
possibly loss at higher doses of the medication because of enhanced noradrenergic effect.

Dual serotonin 2 antagonists/serotonin reuptake inhibitors (Phenylpiperazines)

Trazodone, nafazodone

Action
It blocks the serotonin 2A receptor as well as serotonin uptake. These two agents block serotonin
reuptake to a lesser extent than TCAs/SSRIs. When 5HT-2A receptor are blocked, the normal
inhibiting influence on 5HT-1A receptor is lost, hence these drugs indirectly boost the effect of
stimulating 5HT-1A receptors.

SARIs are relatively safe in overdose. Trazodone is somewhat sedative but can rarely cause
priapism.

Nefazodone was withdrawn from the European market due to hepatotoxicity concerns.