GENERAL DESCRIPTION
Major depression and anxiety is the most common psychiatric disorder. At any given moment 3-5% of the population is depressed. The symptoms of depression are often indirect or unrecognized both by patients and by physicians. Depression is a heterogeneous disorder that has been classified in a number of ways. Drugs used to treat depression are called antidepressants. Any individual who is having several symptoms of depression persistent beyond a few week can be safely treated with antidepressants. Most commonly used antidepressants are second generation SSRIs and SNRIs because of its greater efficacy and safety as compared to older drugs.
PATHOPHYSIOLOGY OF DEPRESSION
The pathophysiology of depression is still not confirmed but several hypothesis have been stated that defines the cause of depression in its own way and method of treatment for depression also defies these hypothesis.
Monoamine hypothesis
This hypothesis states that depression results from the deficiency of one or more key monoamine chemicals which are serotonin, norepinephrine and dopamine. The deficiency of these monoamines then decrease the functional amine-dependent synaptic transmission.
Another hypothesis states that this monoamine chemicals depletion could also cause the post synaptic receptor to upregulate leading to the depression
Lastly the monoamine hypothesis of gene expression suggests that there might be an abnormal functioning gene that is responsible for causing depression.
These hypothesis are simple and give us an idea why antidepressants work.
SYMPTOMS OF DEPRESSION
Major depression may be suspected if few of these symptoms prevail for 2 or more weeks.
Sad mood
Pessimistic thoughts/worry
Diminish interest in normal activities
Insomnia or increase in sleep
Poor concentration
Significant weight loss or gain
Retardation
Feeling of guilt
Feeling of worthlessness
Decrease energy
Libido
Suicidal ideas
TYPES OF ANTIDEPRESSANTS
All currently available antidepressants are classified by the way of their primary actions on metabolism, reuptake, or selective antagonism of serotonin, epinephrine or both except bupropion.
| Class | Generic name | Brand name |
|
SSRIs (Selective Serotonin reuptake inhibitors) |
Citalopram
|
Celexa |
| Escitalopram | Lexapro | |
| Fluoxetine | Prozac | |
| Sertraline | Zoloft | |
| Fluvoxamine | Faverin, Luvox | |
| Paroxetine | Paxil | |
|
SNRIs (Serotonin nor epinephrine reuptake inhibitors) |
Venlafaxine | Effexor |
| Desvenlafaxine | Desfax, Pristiq, Ellefore | |
| Duloxetine
|
Cymbalta | |
| Levomilnacipran
|
Fetzima | |
|
TCA (Tricyclic antidepressants) |
Amitriptyline | Elavil |
| Amoxapine | Asendin, Asendis, Demolox | |
| Clomipramine | Anafranil | |
| Desipramine | Norpramin | |
| Doxepin | Sinequan | |
| Imipramine | Tofranil | |
| Meprotiline | Ludiomil | |
| Nortriptyline | Aventyl, Pamelor | |
| Protriptyline | Vivactil | |
|
MAOIs (Monoamine Oxidase inhibitors) |
Isocarboxazid | Marplan |
| Phenelzine | Nardil | |
| Tranylcypromine | Parnate | |
| Selegiline | Emsam | |
|
Atypical antidepressant |
Bupropion | Wellbutrin |
| Mirtazapine
|
Remeron | |
| Trazodone
|
Desyrel | |
| Nefazodone
|
Serzone | |
| Vilazodone
|
Viibryd | |
| Vortioxetine
|
Trintellix |
MECHANISM OF ACTION OF ANTIDEPRESSANTS:
Antidepressants work by elevating certain neurotransmitter in the brain. At presynaptic serotonergic neuron, this interact with postsynaptic neuron which have postsynaptic receptors which are 5-HT. serotonin is synthesized from amino acid tryptophan by serotonergic neurons. These serotonin is stored in vesicles for regulated release.
At presynaptic noradrenergic neuron, this interact with postsynaptic neuron which have postsynaptic receptors which are β and α1. Norepinephrine is synthesized from amino acid tyrosine by noradrenergic neurons and stored in vesicles awaiting regulated release.
When serotonin and NE release from the neuron they stimulate their receptors and at the same time they transported back to their neurons by a process called reuptake. Serotonin is reuptake by serotonin transporter or SERT and norepinephrine is transported back to their neuron by norepinephrine transporter or NET. Once both chemicals reabsorb they partially repacked in synaptic vesicles in partially broken down into inactive metabolites by an enzyme monoamine oxidase or MAO.
SSRIs
As from the name described these antidepressants selectively inhibit reuptake of serotonin by blocking the SERT which resulted in increased levels of serotonin available to bind postsynaptic 5-HT receptors
SNRIs
SNRIs work by inhibiting both serotonin and norepinephrine reuptake transporter i.e. SERT and NET, which result in increased levels of both serotonin and norepinephrine which can then bind to their respective postsynaptic receptors.
TCAs
This class of antidepressants was named after chemical structure of its compounds which contains three cyclic ring connected together. Its mechanism of action is bit complicated. TCAs inhibit reuptake of both serotonin and norepinephrine by blocking both of their transporter SERT and NET. However different TCAs have different levels of selectivity, some have more selective inhibitor of one transporter like desipramine has more selectivity towards norepinephrine transporter.
TCAs also blocked many other receptors such as α1 receptor of postsynaptic neuron, histamine receptor and muscarinic receptors. It is believed that these blockade of other receptors caused side effects more than their antidepressants activity.
MAOIs
Monoamine oxidase is mitochondrial enzyme that degrades monoamine such as serotonin and epinephrine. MAO enzyme are of two types MAO A and MAO B. They are distributed in brain, gut and liver. MAO A preferably metabolize serotonin but also metabolize norepinephrine and dopamine while MAO B preferably metabolizes dopamine. Therefor inhibition of MAO A may cause antidepressant effects. So mechanism of action of MAOIs is, inhibiting the MAO enzyme preventing breakdown of monoamine neurotransmitter ultimately increasing the availability of these chemicals.
Atypical antidepressants
This class includes agents that have actions at several different sites that is why it doesn’t fit any other class
Bupropion, is a weak norepinephrine and dopamine reuptake inhibitor, besides depression it is found to be effective in reducing nicotine cravings and with drawl symptoms
Mirtazapine is an α2 receptor antagonist, so blocking pre synaptic α2 receptor mirtazapine increases noradrenergic and serotonergic neurotransmission. In addition it also block serotonin receptor at post synaptic neuron and histamine receptor that is why it has sedative effects.
Trazodone and nefazodone has the ability to inhibit SERT and block reuptake of serotonin and also block the serotonin 5HT2A receptor at post synaptic neuron which are the bad serotonin receptor, activation of serotonin 2A receptor contributed in depression. Both of these also inhibits histamine and α1 receptor on pre synaptic neuron that is why it also has sedative effects.
Vilazodone it is serotonin partial agonist reuptake inhibitors means that it partially stimulates serotonin receptors and it inhibits reuptake of serotonin
Vortioxetine it is believe to block SERT at post synaptic neuron and serotonin receptor at pre synaptic neurons
DRUG INTERACTION
Carbamazepine, phenobarbital and phenytoin decrease bupropion levels and increases the level of its active metabolite hydroxybupropion. The concurrent use of valproate and bupropion increase both valproate and hydroxybupropion levels and led to hallucination. Iamotigine when taken with bupropion then cause hypomania.
Bupropion when given with zolpidem then cause visual hallucinations. Bupropion is contraindicated during the abrupt with drawl of antiseizure drugs specially benzodiazepine.
Bupropion when taken with carbimazole, may cause acute liver failure.
Bupropion is contraindicated with MAOI. Selegiline when given concurrently with bupropion then can cause orthostatic hypotension.
Corticosteroid may cause seizures when given concurrently with bupropion.
Methylphenidate may cause grand mal seizure and myocardial infarction when given concurrently with bupropion.
Bupropion is contraindicated with the drug that metabolized by cytochrome CYP450 isoenzyme CYP2D6, CYP2B6.
The concurrent use of alcohol, amantadine, levodopa and nicotine is contraindicated with bupropion.
Pseudoephedrine and nicotine may cause myocardial ischemia when concurrent use with bupropion.
Propranolol increase the toxicity of meprotiline when given concurrently.
Risperidone increase the plasma levels of meprotiline.
Carbamazepine, phenobarbital, phenytoin may decrease the plasma level of mianserin.
Mirtazapine when given with other serotonergic antidepressant, may cause bleeding or serotonin syndrome or hypomania. Two weeks must elapse between the use of mirtazapine and MAOI.
Carbamazepine and phenytoin may decrease the plasma levels of mirtazapine.
The concurrent use of mirtazapine with inducer or inhibitor of cytochrome P450o isoenzyme CYP3A4, then cause pharmacokinetic interaction
Benzodiazepine may increase the sedative effects of mirtazapine when given concurrently.
Cimetidine increases the bioavailability of mirtazapine.
Nefazodone may cause acute hypotension and weakness when given with desipramine, fluoxetine and venlafaxine.
Nefazodone is contraindicated with other serotogenic antidepressants.
The concurrent use of reboxetine and MAOI may cause serious hypertensive crises.
Ketoconazole may inhibits the metabolism of reboxetine. The concurrent use of azoles, macrolides and nefzodone with reboxetine is contraindicated.
Reboxetine may cause hypokalemia when use concurrently with potassium-depleting diuretics.
Rebxoxetine may increase blood pressure when use concurrently with ergot derivatives.
Mild to moderate drowsiness and orthostatic heart rate may cause with the concurrent use of lorazepam and reboxetine.
Cimetidine may increase the plasma level of venlafaxine and duloxetine.
The concurrent use of venlafaxine and propafenone may cause psychosis
Duloxteine is contraindicated with concurrent use of MAOI and SSRIs.
Ciproflozacina, enoxacin and quinidine may increase the plasma levels of duloxetine.
Duloxetine may increase the levels of thioridazine and flecainide
The concurrent use of venlafaxine with co-amoxiclav or dexamphetamine or metoclopramide or tramadol may cause serotonin syndrome.
Diphenhydramine, melperone, quinidine, thioridazine may inhibit the metabolism of venlafaxine.
Venlafaxine and disulfiram may cause hypertensive crisis.
Cyproheptadine may cause oppose the antidepressant effect of fluoxetine.
Cocaine and citalopram may cause multiple drug intoxication.
Dextromethorphan may cause serotonin syndrome or hallucination when given with paroxetine, nefazodone or citalopram.
Grape juice can increase the plasma levels and may cause serotonin like syndrome when given with trazodone, sertraline or fluoxetine.
When paroxetine and sertraline given with ondansetron and dolasetron respectively, may cause serotonin syndrome.
Interferon may reversed the antidepressant effects of paroxetine and trazodone.
Clarithromycin may cause acute fluoxetine toxicity when given concurrently and erythromycin my cause serotonin syndrome when given with sertraline.
Serotonin syndrome may cause when metoclopramide, efavirenz, hydromorphone, oxycodone, pentazocine, pethidine, tramadol, morphine given with SSRIs.
SSRIs may increase the plasma level of protease inhibitors like, ritonavir.
Rifampicin decrease the efficacy of citalopram and sertraline.
Methylphenidate may cause delirium or seizure when given with sertraline. Schizophrenia and amphetamine toxicity may cause when amphetamine and fluoxetine is given concurrently.
Tryptophan may cause central and peripheral toxicity when given with fluoxetine.
Paroxetine when given with barbiturates may cause hepatotoxicity.
Ketoconazole and Itraconazole may inhibit the metabolism of trazodone.
Clarithromycin and ritonavir may impair the trazodone clearance and enhanced its sedative effects.
Pseudoephedrine may cause toxicity when given with trazodone.
Enalapril may cause toxicity when given with TCAs
Fluconazole may increase plasma level, mental changes, syncope, prolong QT interval when given with TCAs
Barbiturates may reduce the plasma levels of TCAs thus reduced the therapeutic effects.
Baclofen may cause multiple sclerosis when given with TCAs
Bupropion may increase the plasma level of TCAs that are metabolized by CYP2D6. Confusion, lethargy, unsteadiness also been reported with their concurrent use.
Diltiazem and verapamil may increase the plasma levels of TCAs possibly accompanied with ECG changes
Tachycardia is observed when cannabis smoked with TCAs
Cimetidine may increase the plasma levels of TCAs
Food may reduce the plasma level and bioavailability of TCAs.
TCAs may cause exaggerated response (hypertension, cardiac arrhythmias etc.) when given with parenteral adrenaline, noradrenaline and less extent to phenylephrine.
Quinidine, ritonavir and propafenone increasing the serum level of TCAs by reducing clearance from the body.
Rifampicin may reduce the level of TCAs.
Venlafaxine may increase the antimuscarinic effects of TCAs.
Terbinafine may increase AUC levels and caused toxicity when given with TCAs
The antidepressant effects of TCAs may be accelerated by the use of thyroid hormone but also can cause atrial tachycardia, thyrotoxicosis, and hyperthyroidism.
Propranolol and labetalol may increase the plasma levels of TCAs
Sucralfate may reduce the absorption of amitriptyline.
NURSING INTERVENTIONS
Enquire the complete health history of the patient including allergy, drug interactions, and family background of depression
Check lab test for CBC, blood glucose, BUN, creatinine, platelets, electrolytes, LFT
Check and identify if any neurological disorder like seizure etc.
Monitor blood pressure and pulse before and during treatment
Administer medicine at night or bed time to avoid drowsiness at day time
Observe mood swing during the treatment
Observe s/s for serotonin syndrome, if any
Observe cardiovascular or neurologic s/s for any disorder, if any
Avoid to administer MAOIs with tyramine containing food
Observe sleep-wake cycle of the patients.
PATIENT EDUCATION
IF taken MAOIs, forbid patient to take any fermented or aged food or containing tyramine.
Advise to take medicine at night or bed time to avoid drowsiness at day time and take morning dose early to avoid insomnia.
Advise patient not to discontinue treatment because it may take 2-4 weeks to start antidepressant effects
Inform the patients about the possible side effects of medication specially serotonin syndrome which may be life threatening.
Report immediately if feeling bradycardia, urinary retention, blurred vision, chest pain, and diaphoresis.
Advice to take care and slow change of posture due to dizziness and danger of fall or injuries.
Avoid driving if feeling drowsiness or dizziness.
Do not breast breast feed while taking medicine.