ANTI DEPRESSANTS

ANTI-DEPRESSANTS

Depression is a serious disorder that afflicts in adults throughout the world. Anti depressions are used to treat the depression.

Symptoms of depression: Hopelessness, feelings of sadness, and despair, loss of energy, changes in sleep patterns, appetite, and suicidal thoughts.

Mechanism of action of antidepressants: According to the monoamine hypothesis of depression postulates a deficiency in serotonin or nor-epinephrine neurotransmission in the brain. Most of the currently used antidepressants work by slowing the removal of both nor-epinephrine and serotonin from the brain, thus increasing the availability of these neurotransmitters. As a result, they are efficacious for patients whose depression is caused by the imbalance of either nor-epinephrine or serotonin.

Drug therapy for antidepressants:

1. TCAs (Tri-cyclic antidepressants): Amitriptyline, Clomipramine, Desipramine, Doxepin,  Dothiepin, Imipramine, Melitracen,  Nortriptyline, Trimipramine.
2. Tetracyclic antidepressants: Mianserin, Maprotiline.
3. SSRIs (Selective Serotonin Reuptake Inhibitors): Fluoxetine, Paroxetine, Sertraline,  

Fluvoxamine, Citalopram, Escitalopram.

1. SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors): Venlafaxine/ Venlafaxine XR, Duloxetine.
2. Atypical antidepressants: Mirtazapine.
3. MAOIs (Monoamine Oxidase Inhibitors): Moclobemide, Phenelzine, Isocarboxazid,     

      Tranylcypromine.

1. Lithium salts: Lithium carbonate.

Tri-cyclic Antidepressants: The TCAs (tri-cyclic antidepressants) blocks serotonin and nor-epinephrine reuptake into the neuron. The TCAs include the tertiary amines amitriptyline, clomipramine, doxepin, imipramine, and trimipramine and the secondary amines include desipramine, nor-triptyline and protriptyline. All the drugs have similar therapeutic efficacy and the choice of drugs depend upon patient prior response, tolerance, preexisting medical conditions, and duration of action.

Mechanism of action:

• Blocking of receptors: Amoxapine also blocks the D2 receptor.TCAs also block adrenergic, histaminic, serotonergic, and muscarinic receptors.
• Inhibition of neurotransmitter reuptake: TCAs and amoxapine are potent inhibitors of the neuronal reuptake of nor-epinephrine and serotonin into presynaptic nerve terminals. The TCAs cause increased concentrations of monoamines in the synaptic cleft, ultimately resulting in antidepressant effects, by blocking the major route of neurotransmitter removal. At therapeutic concentrations, TCA does not block dopamine transporters. Desipramine and maprotiline are the selective inhibitors of nor-epinephrine reuptake.

Pharmacokinetics: These are well absorbed upon orally, widely distributed and readily penetrate into the CNS. These drugs are metabolized by the hepatic microsomal system and excreted as inactive metabolites via the kidney.

Side effects: Dizziness, blurred vision, constipation, dry mouth, headache, sweating, tremor, palpitation, difficulty passing urine, liver dysfunction, orthostatic hypotension, seizure, ECG changes and abnormal blood count.

Therapeutic uses: Cardiac arrhythmias and other serious cardiovascular problems, effective in treating moderate to severe major depression, used to treat migraine headache and chronic pain syndromes.

Mianserin: It was originally designed as an anti-allergic drug, subsequently, a variety of clinical trials have indicated that Mianserin possesses antidepressant activity equal to that of the widely used tri-cyclic antidepressants. It is a tetra-cyclic compound structurally distinct from both the classical tri-cyclic antidepressants and from bridged tri-cyclic of the maprotiline type.

 Selective Serotonin Reuptake Inhibitors: The selective serotonin reuptake inhibitors (SSRIs) are a group of chemically diverse antidepressant drugs that specifically inhibit serotonin reuptake, having 300- to 3000-fold greater selectivity for the serotonin transporter as compared to the nor-epinephrine transporter. SSRIs include citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline. Escitalopram is the pure S-enatiomer of citalopram. Both citalopram and fluoxetine are racemic mixtures, of which the respective S-enantiomers are the more potent inhibitors of the serotonin reuptake pump. The SSRIs block the reuptake of serotonin, leading to increased concentrations of the neurotransmitter in the synaptic cleft and, ultimately, to greater postsynaptic neuronal activity.

Pharmacokinetics: Food has little effect on absorption. All of the SSRIs are well absorbed after oral administration. Peak levels are seen in approximately 2- 8 hours on average.

Side effects: Anxiety, dry mouth, headache, nausea, vomiting, gastrointestinal discomfort, somnolence, tremor, sweating, sexual dysfunction and weight loss, etc. Occasionally, some patients may experience insomnia, excitement, restlessness or seizure.

Therapeutic uses: Used to treat psychiatric disorders, posttraumatic stress disorder, panic disorder, generalized anxiety disorder, social anxiety disorder, and bulimia nervosa.

Serotonin-Nor-epinephrine Reuptake Inhibitors: These agents, termed selective serotonin-nor-epinephrine reuptake inhibitors (SNRIs), may be effective in treating depression in patients in whom SSRIs are ineffective.

Venlafaxine: It is a potent inhibitor of serotonin reuptake and, at medium to higher doses, is an inhibitor of nor-epinephrine re-uptake. It is also a mild inhibitor of dopamine reuptake at high doses. Venlafaxine has minimal inhibition of the cytochrome P450 isoenzymes and is a substrate of the CYP2D6 isoenzyme.

Side effects: Headache, nausea, dizziness, sexual dysfunction, insomnia, sedation, and constipation. At high doses, increase in blood pressure and heart rate.

 Duloxetine: It inhibits the serotonin and nor-epinephrine reuptake at all doses. It is extensively metabolized in the liver to numerous metabolites. Metabolites are excreted in the urine, and the use of duloxetine is not recommended in patients with end-stage renal disease and it should not be administered to patients with hepatic insufficiency.

Side effects: Constipation, dry mouth, nausea, diarrhea, sexual dysfunction and weight loss, vomiting, insomnia, dizziness, somnolence, and sweating are also seen. These drugs may cause hypertension at high doses.

Mirtazapine: This drug enhances nor-epinephrine and serotonin neurotransmission via mechanisms related to its ability to block presynaptic receptors. Mirtazapine is markedly sedating, which may be used to advantage in depressed patients having difficulty sleeping.

Monoamine Oxidase Inhibitors: MAO is a mitochondrial enzyme found in nerve and other tissues, such as the liver and gut. The MAO inhibitors may reversibly or irreversibly inactivate the enzyme, permitting neurotransmitter molecules to escape degradation and, therefore, to both accumulate within the presynaptic neuron and leak into the synaptic space. 3 MAO inhibitors are currently available for treatment of depression: selegiline, which is the first antidepressant available in a transdermal delivery system, phenelzine and tranylcypromine, the agent that was prior-approved for Parkinson's disease, but is now also approved for depression.

 Mechanism of action: These drugs inhibit not only MAO in the brain but also MAO in the liver and gut that catalyze oxidative deamination of drugs and potentially toxic substances, such as tyramine, which is found in certain foods. Most MAO inhibitors, such as phenelzine, form stable complexes with the enzyme, causing irreversible inactivation. This results in increased stores of serotonin, nor-epinephrine, and dopamine within the neuron and subsequent diffusion of excess neurotransmitter into the synaptic space.

Pharmacokinetics: These drugs are well absorbed orally, metabolized and excreted rapidly in the urine.

Side effects: Dizziness, headache, nervousness, gastrointestinal disturbance, sweating, vomiting and hypertensive crisis.

Therapeutic uses: Useful in the treatment of phobic states, atypical depression.

Lithium carbonate: This medication is used to treat manic-depressive disorder (bipolar disorder). It works to stabilize the mood and reduce extremes in behavior by restoring the balance of certain natural substances (neurotransmitters) in the brain.

Side effects of Lithium salts: Bitter taste, dry mouth, tremor, polyuria, fatigue and weight gain. Other less-common side effects include hyperthyroidism, hypothyroidism, ECG changes, raised anti-diuretic hormone concentrations, renal failure or leucocytosis.

Depression, typical depressants, atypical depressants, mao inhibitors