Anti-Depressant Medications A Introduction: This topic may be a little bit underestimated here in Jordan, while in western countries it has more significance. The function of anti-depressants is to change your mood from So, what is Depression? It s a mental illness that is always related to: Psychological diseases as: Low mood Loss of interest Reduce energy Feel of guilt Worthlessness Physiological symptoms as: Sleep disturbances Decrease appetite Decrease libido In the worst scenarios, it may lead to suicide and psychosis. 1
A Types of Depression Refractory (secondary): It has some predisposing factors; as losing a relative or a friend, failing an exam, or during wars. It is normal, and there are many treatments for it. (not the depression we ll talk about) Major depression disorder: It s of an endogenous origin (No predisposing factors). It s not associated with life events. (Nobody knows the reason). Also maybe hereditary. Bipolar disorder: (Sometimes happy, sometimes depressed) It has a mixed alternating episodes of elevated mood and depression. A Physiological Basis of Depression Anti-depressants potentiate, directly or indirectly, the action of NE and/or 5-HT (serotonin) in the brain. So what are the pros and cons against this theory? Reserpine depletes serotonin and catecholamines. Decreased levels of MOPEG (NE metabolite) in urine of depressed individuals. Decreased levels of 5-HIAA (Serotonin metabolite) in CSF in a subset of depressed individuals. Antidepressants increase the NT in the synapse by: Inhibiting degradation by (MAOI) and (COMTI) Inhibiting reuptake by (SSRI; SNRI) Anti-depressants raise NE and 5-HT immediately; however, their therapeutic action is delayed. Not all anti-depressants increase NE and/or 5-HT in the synapse. Cocaine and amphetamine are not effective anti-depressants. 2
A Anti-depressants: MAO inhibitors Tricyclic antidepressants Second generation antidepressants: SSRIs Selective Serotonin Reuptake Inhibitors SNRIs Serotonin Norepinephrine Reuptake Inhibitors Atypical antidepressants A General principles of Anti-depressants therapy The maximum therapeutic effect is usually delayed. Classes are different by their side effects mainly. Patients do not respond equally to medications. If the patient does not respond to one medication, change or use combination. All Anti-depressants can produce mania. Suicide is always a potential outcome. Serotonin (5-HT) structure and relation to anti-depressants 3
Norepinephrine (NE) structure and relation to anti-depressants ; MAO enzymes Two types of MAO enzyme: MAO-A: (non-selective) Deactivates dopamine, NE, and 5-HT It s a target for Antidepressants MAO-B: (selective) Dopamine deactivation. No 5-HT or NE effect. Causes Parkinson s disease. ; MAO Inhibitors They bind irreversibly to the enzyme Examples on non-selective drugs: (inhibit both MAOA & MAOB) Phenelzine Tranylcypromine Isocarboxazide Examples on selective drugs: MAOA Inhibitors: moclobemide (not commonly used) MAOB Inhibitors: Selegiline (also used in Parkinson s disease) 4
S/E: Hypertension: due to the increased NE in the body. One of the reasons is consuming tyramine containing food (as bananas, cheese and red wine), because it is a catecholamine releaser (a compound that looks like catecholamines that displace them from the vesicles causing depletion). The treatment in this case is: Prazocin and phentolamine. Combination with SSRI causing Serotonin syndrome that leads to: High BP, tremor Hyperthermia Seizures Metabolic acidosis ; Tricyclic antidepressants (TCA) They inhibit the reuptake of NE and 5-HT. They can also block H1, M, and Alpha 1 receptors causing side effects. Examples: Imipramine Desepramine Amitriptyline Nortriptyline No effect on normal individuals. Helpful to treat enuresis (specifically Imipramine) by blocking M receptors or blocking rapid eye movement (REM) during sleep. 5
May be helpful in Migraine and Neuropathic pain (Amitriptyline). Pharmacokinetics: Absorbed orally. Metabolized in the liver. S/E: Antimuscarinic effects: Vision problems (dilatation of pupils), decrease salivation, decrease urination, etc. Cardiac arrhythmias Alpha 1 antagonist effect leading to postural hypotension and tachycardia. Antihistamine: Producing sedation and weight gain. ; SSRIs Selective Serotonin Reuptake Inhibitors It s the first-line treatment for depression. NO muscarinic, alpha-adrenergic, or histamine effects. Other uses: OCD (Obsessive Compulsive Disorder) PTSD (Post Traumatic Stress Disorder) Panic disorder Generalized anxiety disorder Pharmacokinetics: Orally absorbed Metabolized in liver 6
Half-life varies: Fluoxetine is the longest, it s the DOC in children and it can produce active metabolites, and may inhibit liver enzymes. Excreted through the kidneys. Drugs: Citalopram Fluoxetine (young) Escitalopram, sertraline (adult) S/E: Sleep disturbances Sexual dysfunction (The main significant side effect) Suicidal thoughts Hyponatremia (In elderly) Discontinuation syndrome: (when you stop taking the drug) Headache, malaise, nervousness, sleep disturbances. More with short acting drugs. Fluoxetine is the safest. ; SNRIs Serotonin Norepinephrine Reuptake Inhibitors MOA is similar to TCA, but the difference is that they are not tricyclic compounds and they don t have an effect on M receptors, Alpha receptors, or histamine receptors. Examples: Duloxetine and venlafaxine S/E: Similar to SSRIs May increase blood pressure, sweating, and urinary retention. 7
; Atypical Antidepressants Examples are: Bupropion It can block NE Transporters and Dopamine Transporters. Mainly used in nicotine dependence. Terminal-illness (used in end stage cases of cancer) Side effects related to sympathomimetic effect Trazodone: 5-HT receptor antagonist & SERT inhibitor (Serotonin Transporter Inhibitor) It has no anticholinergic effects A Bipolar disorder Mixed disorder with Depressive phase and manic phase: (Nafseya) Little sleep Talk rapidly and non-stop Mania without depression extremely rare. DOC is Lithium: Effective against the majority of the cases. Requires several weeks for full effect. Does not affect the mood of normal people. MOA is not well known. Has narrow therapeutic index Needs drug monitoring. 8
S/E: CNS-related: Headache, dizziness, fatigue, etc. Nephrogenic diabetes insipidus, because they compete on the ADH receptors. Inhibit TSH: Leading to Hypothyroidism. Teratogenic in humans. Other medications: (used for maintenance) Anticonvulsants: Carbamazepine Valproic acid Lamotrigine Antipsychotics: Second generation (Atypical) such as: Olanzapine, and resperidone 9