Antidepressants

AntidepressantsClassification1. Reversible inhibitors of MAO-A (RIMAs)

• Moclobemide, clorgyline

2. Tricyclic antidepressants (TCAs)

• NA + 5-HT reuptake inhibitors: Imipramine, Amitriptylline, Trimipramine, Doxepin, Dothiepin, Clomipramine
• Predominantly NA reuptake inhibitors: Desipramine, Nortriptylline, Amoxapine, Reboxetine

3. Selective serotonin reuptake inhibitors (SSRIs)

• Fluoxetine, fluvoxamine, Paroxetine, Sertraline, Citalopram, Escitalopram, Dapoxetine

4. Serotonin and noradrenaline reuptake inhibitors (SNRIs)

• Venlafaxine, Duloxetine

5. Atypical antidepressants

• Trazodone, Mianserin, Mirtazapine, Bupropion, Tianeptine, Amineptine, Atomoxetine

 MAO inhibitors ​MAO is a mitochondrial enzyme involved in the oxidative deamination of biogenic amines (Adr, NA, DA, 5-HT)MAO inhibitors drugs include:

• Isoniazid
• Iproniazid
• Phenelzine
• Isocarboxacid
• Tranylcypromine
• Selegiline selectively inhibit MAO-B at low doses and not effective as antidepressant. At high doses, it become non selective MAO inhibitor – exhibits antidepressant and excitant properties.

 Reversible inhibitors of MAO-A (RIMAs) Moclobemide 

• Reversible and selective MAO-A inhibitor with short duration of action
• It lacks anticholinergic, sedative, cognitive, psychomotor and cardiovascular adverse effects of typical TCAs and is safer in overdose. 
• RIMAs have a limited but useful role in the differential therapeutics of the depressive disorders. Moclobemide is as effecrive as tricyclic antidepressants bit are better tolerated. Moclobemide is less effective but better tolerated than older MAOIs like phenelzine or tranylcypromine. ⁽¹⁾
• Tyramine evoked mydriasis by moclobemide reflects the inhibition of MAO-A activity in the iris. ⁽²⁾
• Moclobemide is an effective antidepressant and is better tolerated than imipramine. ⁽³⁾
• It is a reversible MAO A inhibitor, Monoamine oxidase type B activity in the platelets is slightly and transiently inhibited after administration of moclobemide. The secretion of prolactin is dose dependently stimulated while plasma concentration of growth hormone and cortisol remain unchanged. ⁽⁴⁾
• The combination of moclobemide overdose with reuptake blockers will sufficiently enhance neurotransmission to produce fatalities. ⁽⁵⁾
• The antidepressant effects of moclobemide is seen in depressed patients with Parkinson’s disease. The combination of moclobemide and selegiline have a more pronounced efficacy on mood and cognitive performances. ⁽⁶⁾
• Moclobemide is a short acting and reversible MAO inhibitor. It is a novel and safe drug for the treatment of affective disorders. ⁽⁷⁾
• Concomitant treatment with moclobemide and selegiline have a supra-additive effect on the sensitivity of intravenously administered tyramine, the combination therapy should be considered when accompanied by dietary restrictions. Concomitant therapy with moclobemide and levodopa/benseraaide is well tolerated. When oral ephedrine is added to steady state moclobemide treatment, the cardiovascular effects are increased. ⁽⁸⁾
• Moclobemide lacks anticholinergic activity and differs from classic MAO inhibitors by potentiating only weakly the pressor effect of p.o. tyramine. ⁽⁹⁾
• Used in elderly patients and patients with heart disease
• Adverse effects:

o Nausea, dizziness Headache Insomniao Excitemento Liver damage  Tricyclic antidepressants (TCAs) 

• NA + 5-HT reuptake inhibitors: Imipramine, Amitriptylline, Trimipramine, Doxepin, Dothiepin, Clomipramine
• Predominantly NA reuptake inhibitors: Desipramine, Nortriptylline, AMoxapine, Reboxetine

Pharmacological action ​The predominant action of TCAs is their ability to inhibit norepinephrine transporter (NET) and serotonin transporter (SERT) located at neuronal/ platelet membrane at low and therapeutic attained concentrations 1. CNS

• In normal individuals: it induces peculiar clumsy feeling, tiredness, light headedness, sleepiness, difficulty in concentrating and thinking and unsteady gait
• In depressed patients: little acute effects are produced. After 2-3 weeks of continuous treatment, the mood is gradually elevated. REM sleep phase and awakening during night are reduced.
• TCA lower seizure threshold and produce convulsion in overdose. Clomipramine and bupropion have highest seizure precipitating potential.
• Amitriptyline and imipramine depress respiration in overdose only. 

2. ANS​

• Most TCA are potent anticholinergic- cause dry mouth, blurring of vision, constipation and urinary hesitancy as side effects
• They potentiate exogenous and endogenous NA by blocking uptake, but also have weak α1 adrenergic blocking action

3. CVS

• Effects on cardiovascular function are predominant
• Tachycardia: due to anticholinergic and NA potentiating actions
• Postural hypotension: due to inhibition of cardiovascular reflexes and α1 blockade
• ECG changes and cardiac arrhythmias: T wave suppression or inversion. Arrhythmias occur in overdose mainly due to interference with intraventricular conduction.

Tolerance and dependence

• Tolerance to anticholinergic and hypotensive effects of imipramine like drugs develop gradually, but antidepressant action is sustaine.
• Psychological dependence on these drugs is rare
• Physical dependence occurs when high doses are used for a long period- malaise, chills, muscle pain may occur on discontinuation and have been considered withdrawal phenomena
• Desipramine is an active metabolite of imipramine used in the treatment of depressive illness is different and less active drug. Imipramine is preferred over desipramine in the treatment of depressive illness. ⁽¹⁰⁾
• The use of imiprmaine/chloropyramine combination in first trimester is associated with congenital malformation in the fetus. ⁽¹¹⁾
• Imipramine prolongs PR, QQRS and QTc intervals, increases the heart rate and lowers T wave amplitude. It also has a potent antiarrhythmic action in patients who are recovering from depression. ⁽¹²⁾
• Imipramine has tissue-dependent effect on FFA and can be useful tool for improvement of neutral lipids levels and insulin resistance in skeletal muscle of old animal. ⁽¹³⁾
• Imiprmaine is a valuable addition in the treatment of absence and myoclonic-astatic seizures which do not respond to conventional medications. ⁽¹⁴⁾
• Early in the night, when the sleep is deepest, imipramine decreases bladder excitability and/or increases the chil’s bladder capacity. It also results in moderate degree of rapid eye movement (REM) suppression. With long term administration, there is dimunition of REM suppressant effect. ⁽¹⁵⁾
• Imipramine improves the symptoms of patients with chest pain and normal coronary angiograms through a visceral analgesic effect. ⁽¹⁶⁾
• Unexpected deaths have occured in patients with cardiac disease receiving amitriptylline. Thus amitryptilline should be used with caution with cardiac disease. ⁽¹⁷⁾
• Amitriptyline intoxication in children causes respiratory insufficiency, arrhythmias and hypotension, which disappear with only supportive treatment. ⁽¹⁸⁾
• Amitriptylne is less well tolerated than tricyclics/ heterocyclics and SSRI’s but slightly more patients treated on it recover than on alternative antidepressants. ⁽¹⁹⁾
• Amitriptyline is an effective antimigraine agent and the antimigraine effect is relatively independent of antidepressant activity. ⁽²⁰⁾

Pharmacokinetics

• Oral absorption of TCA is good, though often slow
• They are highly bound to plasma and tissue proteins, therefore have large volumes of distribution
• They are extensively metabolized in liver; major route for imipramine and amitriptyline is demethylation whereby active metabolite- desipramine and nortriptyline respectively are formed
• Metabolites are excreted in urine over 1-2 weeks
• The plasma t ½ of amitriptyline, imipramine and doxepin range 16-24 hours
• An unusual therapeutic window phenomenon has been observed- optimal antidepressant effect is exerted at a narrow band of plasma concentrations (between 50-200 ng/ml of imipramine, amitriptyloine, nortriptyline). Bith below and above this range, beneficial effects are suboptimal.

 Adverse effects

• Anticholinergic: dry mouth, bad taste, constipation, epigastric distress, urinary retention, blurred vision, palpitation
• Sedation, mental confusion and weakness
• Increased appetite and weight gain
• Some patients receiving antidepressant may abruptly switch over to a dysphoric agitated state or to mania
• Sweating and fine tremors
• Postural hypotension, especially in older patients
• Sexual distress: especially delay or interference with erection, ejaculation and occasionally orgasm
• Cardiac arrhythmias, especially in patients with ischemic heart disease
• Rashes and jaundice due to hypersensitivity are rare

Interactions

• TCA potentiate directly acting sympathomimetic amines. Adrenaline containing local anesthetic should be avoided
• TCA abolish the antihypertensive action of guanethidine and clonidine by preventing their transport into adrenergic neurons
• TCAs potentiate CNS depressants, including alcohol and antihistaminics
• Phenytoin, phenylbutazone, aspirin and CPZ can displace TCAs form protein binding sites and can cause transient overdose symptoms
• Phenobarbitone competitively inhibits as well as induces imipramine metabolism
• SSRIs inhibit metabolism of several drugs including TCAs- dangerous toxicity occurs if two are given concurrently
• TCA delay gastric emptying and retard their own as well as other drug’s absorption. Digoxin and tetracyclines may be more competitively absorbed
• MAO inhibitors-  dangerous hypertensive crisis with excitement and hallucination has occurred when given with TCAs

 Selective serotonin reuptake inhibitors (SSRI)

• Produce little or no sedation, do not interfere with cognitive and psychomotor function or produce anticholinergic side effects  
• They are devoid of α adrenergic blocking action- postural hypotension does not occur
• They have practically no seizure precipitating propensity and do not inhibit cardiac conduction – overdose arrhythmias are not a problem
• Chronic administration of fluoxetine reinstates ocular dominance plasticity in adulthood and promotes recovery of visual functions in adult amblyopic animals. ⁽²¹⁾
• The exposure to fluoxetine during adolescnce modulates responsiveness to emotion eliciting stimuli in adulthood via long lasting adaptations in extracellular signal regulated kinase (ERK) related signalling within the ventral tegmental area (VTA). ⁽²²⁾
• Dose dependent seizureacitivity is seen with fluoxetine therapy. The other predisposing factors include family history, underlying neurological problems, concurrent medications, substance abuse and rapid increments in the dose. ⁽²³⁾
• The serotonin system of the developing brain is highly sensitive to in utero exposure to fluoxetine. It modulates the serotonin system in the brain. ⁽²⁴⁾
• Fluoxetine is not associated with an increased risk of suicidal acts or emergence of substantial suicidal thoughts among depressed patients. ⁽²⁵⁾
• Fluoxetine selectively inhibits serotonin uptake in vitro and in vivo and thus enhances serotonergic function, leading to decrease in food intake beginning with the first dose and a decrease in body weight or in weight gain after multiple dose. It has a potential use in weight reduction programs in obese humans. ⁽²⁶⁾
• Fluoxetine facilitate the recovery in poststroke patients undergoing rehabilitation. It has a better functional outcome from stroke than physical therapy alone. ⁽²⁷⁾
• Fluoxetine is effective and well tolerated in the prevention of post-traumatic stress disorder relase for up to 6 months. ⁽²⁸⁾
• Fluoxetine therapy is associated with hypersensitivity oneumonitis associated with pulmonary phospholipidosis. ⁽²⁹⁾
• Side effects are

Gastrointestinal: nausea, loose motion More commonly interfere with ejaculation or orgasm Nervousness, restlessness, insomnia, anorexia, dyskinesia and headache Epistaxis and ecchymosis Gastric blood loss due to NSAIDs may be increased by SSRIs

• Serotonin syndrome: when any serotonergic drug (MAOIs, tramadol, pethidine) is taken by a patient taking SSRIs. The manifestations are:

Agitation, Restlessness, Rigidity, Hyperthermia, Delirium, Sweating, Twitching followed by convulsion

• Discontinuation reaction consist of paresthesias, bodyache, bowel upset, agitation and sleep disturbances

 Uses of antidepressants

1. Endogebous (major) depression
2. Obsessive-compulsive and phobic states
3. Anxiety disorders
4. Neuropathic pain
5. Attention deficit hyperactivity disorder (ADHD) in children
6. Premature ejaculation
7. Enuresis
8. Migraine
9. Pruritis

Summary 

References:

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