Antidepressant Drugs Flashcards
Sertraline
SELECTIVE SEROTONIN-REUPTAKE INHIBITORS (SSRIs)
Clomipramine and Desipramine and Imipramine
TRICYCLIC ANTIDEPRESSANTS (TCAs)
Isocarboxazid
MAOIs
ALTERNATIVES TO LITHIUM
Valproate and carbamazepine are widely used.
The atypical antipsychotics olanzapine and aripiprazole are approved for maintenance treatment of bipolar disorder.
Other atypical antipsychotics (quetiapine, risperidone) are approved for treatment of acute mania or mixed episodes.
A combination of olanzapine with fluoxetine has been approved for treatment of depression associated with bipolar disorder.
Lamotrigine is approved for maintenance treatment in bipolar disorder.
Liver function and CBC should be monitored in patients taking valproic acid.
CBC should be monitored in patients taking carbamazepine.
Duloxetine
SEROTONIN & NOREPINEPHRINE REUPTAKE INHIBITORS (SNRIs)
Mirtazapine
NORADRENERGIC & SPECIFIC SEROTONERGIC ANTIDEPRESSANTS (NASSA)
MIRTAZAPINE
Mirtazapine is a potent antagonist of central presynaptic α2-adrenergic receptors, and thus enhances release of norepinephrine and 5-HT.
Additionally, it is an antagonist at 5-HT2 and 5-HT3 receptors.
Mirtazapine is also a potent H1 antagonist, which is associated with sedation and weight gain.
Mirtazapine may be useful when insomnia or agitation is prominent.
MAOIs
Actions and Uses
1. MAOIs - Actions and Uses
ISOCARBOXAZID, PHENELZINE, TRANYLCYPROMINE, SELEGILINE
Monoamine oxidase (MAO) is a mitochondrial enzyme found in nerve and other tissues, such as the gut and liver. In the neuron, MAO functions as a “safety valve” to oxidatively deaminate and inactivate any excess neurotransmitter molecules (norepinephrine, dopamine, and serotonin) that may leak out of synaptic vesicles when the neuron is at rest.
There are two isozymes of MAO: MAO-A and MAO-B. MAO-A preferentially deaminates norepinephrine, and serotonin. Dopamine and tyramine are metabolized by both isozymes.
The antidepressant effect of MAOIs correlates with inhibition of MAO-A. MAO inhibitors currently available for treatment of depression are: the hydrazine derivatives phenelzine and isocarboxazid, and the non-hydrazines tranylcypromine and selegiline.
MAO inhibitors inactivate the enzyme, permitting neurotransmitter molecules to escape degradation and, therefore, to both accumulate within the presynaptic neuron and leak into the synaptic space. This is believed to cause activation of norepinephrine and serotonin receptors, and it may be responsible for the indirect antidepressant action of these drugs.
Phenelzine, isocarboxazid, and tranylcypromine bind irreversibly and nonselectively to MAO-A and MAO-B.
The MAO-B inhibitor selegiline is approved for treatment of early Parkinson’s disease. Selegiline has also antidepressant effects, particularly at high doses that also inhibit MAO-A. Selegiline is the first antidepressant available in a transdermal delivery system.
ACTIONS
Although MAO is fully inhibited after several days of treatment, the antidepressant action of the MAO inhibitors is delayed several weeks.
Selegiline and tranylcypromine have an amphetamine-like stimulant effect that may produce agitation or insomnia.
USES
MAO inhibitors are now rarely used in clinical practice due to toxicity and potentially lethal food and drug interactions. Their primary use is in the treatment of depression unresponsive to other antidepressants.
Lithium
DRUGS FOR BIPOLAR DISORDER
LITHIUM
Lithium is the standard treatment for bipolar disorder. Used prophylactically in treating manic- depressive patients and in treatment of manic episodes. Also effective in 60-80% patients with mania and hypomania. Lithium is clinically effective at a plasma concentration of 0.5 – 1mM; above 1.5 mM it produces a variety of toxic effects, so the therapeutic window is narrow.
MECHANISM OF ACTION
The inositol depletion theory is the most widely accepted explanation for the actions of lithium.
G protein-linked receptors which couple to Gq activate phospholipase C, which cleaves PIP2 to yield DAG and IP3. IP3 signaling is terminated by conversion to IP2 by IP3 phosphatase. IP2 is converted to IP1 by inositol polyphosphatase, and IP1 is then converted to free inositol by inositol monophosphatase.
Lithium inhibits both inositol polyphosphatase and inositol monophosphatase, thus blocking the regeneration of inositol. Free inositol is essential for the synthesis of PIP2, therefore lithium blocks the phosphatidylinositol signaling cascade in the brain.
Inositol circulates freely in blood, but it cannot cross the blood-brain barrier. The two mechanisms of inositol synthesis which exist in CNS neurons: regeneration from IP3 and de novo synthesis from glucose-6-phosphate, are both inhibited by lithium.
By blocking the regeneration of PIP2, lithium inhibits central adrenergic, muscarinic, and serotonergic neurotransmission.
Inhibition by lithium is uncompetitive, therefore only neurons with active receptors will be affected by lithium. In those neurons, PIP2 levels will decrease, and PLC-coupled receptors will become inactive. This prevents actions of neurotransmitters responsible for mood swings. The hypothesis explains why lithium is brain-selective. But it doesn’t give clues as to which neurotransmitter is involved.
PHARMACOKINETICS
Lithium is given by mouth as the carbonate salt. Lithium is absorbed rapidly and completely from the gut. The drug is distributed throughout the body water and cleared by the kidneys. The half-life is about 20 h. Plasma levels must be monitored.
Selegiline
MAOIs
SELECTIVE SEROTONIN-REUPTAKE INHIBITORS (SSRIs)
Adverse Effects, Drug Interactions and Overdoses
PHARMACOKINETICS
All of the SSRIs are well absorbed after oral administration. Only sertraline undergoes significant first-pass metabolism. All SSRIs are well distributed.
The majority of SSRIs have plasma half-lives that range between 16 and 36 hours. Fluoxetine differs from the other members of the class in two respects. First, it has a much longer half-life (50 hours). Second, the metabolite of the S-enantiomer, S-norfluoxetine, is as potent as the parent compound. The half-life of the metabolite is quite long, averaging 10 days.
Excretion of the SSRIs is primarily through the kidneys, except for paroxetine and sertraline, which also undergo fecal excretion (35 and 50 %).
Dosages of all of these drugs should be adjusted downward in patients with hepatic impairment.
ADVERSE EFFECTS
Increased serotonergic activity in the gut is commonly associated with nausea, GI upset, diarrhea and other GI symptoms.
Increased serotonergic tone at the level of the spinal cord and above is associated with diminished sexual function and interest. As a result, 30-40% of patients on SSRIs report loss of libido, delayed orgasm, or diminished arousal.
Other adverse effects related to the serotonergic effects of SSRIs include increase in headaches and insomnia or hypersomnia. Some patients gain weight when taking SSRIs, particularly paroxetine.
DRUG INTERACTIONS
Fluoxetine and paroxetine are potent inhibitors of CYP2D6 and therefore have high potential for drug interactions. CYP2D6 is responsible for the elimination of TCAs, neuroleptic drugs, and some antiarrhythmic and β-blockers.
Fluvoxamine is an inhibitor of CYP1A2, CYP2C19 and CYP3A4 and therefore it also has high potential for drug interactions.
Citalopram, escitalopram and sertraline have low potential for interactions.
All SSRIs have the potential to cause a serotonin syndrome when used in the presence of a MAO inhibitor or another serotonergic drug. Therefore, extended periods of washout for each drug class are needed prior to the administration of the other class of drugs.
OVERDOSES
Large intakes of SSRIs do not usually cause cardiac arrhythmias (compared to the arrhythmia risk for the TCAs), but seizures are a possibility because all antidepressants may lower the seizure threshold.
The likelihood of fatalities from SSRI overdoses is extremely low.
DISCONTINUATION SYNDROME
Sudden withdrawal of SSRIs can precipitate a discontinuation syndrome. Antidepressant discontinuation syndrome is most often seen in the primary care office in association with SSRI discontinuation, because SSRIs are the most commonly prescribed class of antidepressant medications. The symptoms include nervousness, anxiety, irritability, tearfulness, electric-shock sensations, dizziness, insomnia, confusion, and nausea. This syndrome is most likely to occur with a short half-life drug, such as paroxetine. It is less likely to occur with fluoxetine, due to its long half-life.
Lithium Adverse Effects and Drug Interactions
ADVERSE EFFECTS
Acute lithium toxicity results in various neurological effects, progressing from confusion and motor impairment, to coma, convulsions and death if the plasma concentration reaches 3 – 5 mM.
Main adverse effects include:
Tremor, sedation, ataxia, and aphasia. Propranolol and atenolol can alleviate lithium- induced tremor.
Seizures.
Weight gain.
Hypothyroidism.
Nephrogenic diabetes insipidus. When lithium-induced nephrogenic diabetes insipidus is diagnosed, lithium should be discontinued, if possible. If lithium therapy cannot be discontinued amiloride should be administered. Amiloride inhibits epithelial sodium chanels in collecting tubule cells and minimizes further accumulation of lithium. Other therapeutic options to manage polyuria in lithium-induced nephrogenic diabetes insipidus are: thiazides and NSAIDs. Thiazides diminish distal water delivery and cause mild volume depletion. NSAIDs decrease synthesis of prostaglandins. Prostaglandins antagonize the action of ADH, therefore NSAIDs increase concentrating ability.
Edema.
Dermatitis.
Alopecia.
Leukocytosis.
Acute intoxication is characterized by vomiting, profuse diarrhea, coarse tremor, ataxia, coma, and convulsions.
The use of lithium during pregnancy may increase the incidence of congenital cardiac anomalies. Category D. Contraindicated in nursing mothers.
MONITORING
Serum lithium concentrations, and thyroid, and renal function should be regularly monitored.
DRUG INTERACTIONS
Renal clearance of lithium is reduced by diuretics, and doses may need to be reduced.
By altering renal perfusion, NSAIDs can facilitate renal proximal tubular resorption of lithium and thereby increase lithium serum concentrations
ACE inhibitors and ARBs also can cause lithium retention.
SELECTIVE SEROTONIN-REUPTAKE INHIBITORS (SSRIs)
Actions and Uses
SSRIs are a group of chemically diverse antidepressant drugs that specifically inhibit serotonin reuptake.
They have 300- to 3000-fold greater selectivity for the serotonin transporter as compared to the norepinephrine transporter. This contrasts with the TCAs that nonselectively inhibit the uptake of norepinephrine and serotonin.
Additionally, SSRIs have little blocking activity at muscarinic, α-adrenergic, and histaminic H1 receptors. Therefore, common side effects associated with TCAs, such as orthostatic hypotension, sedation, dry mouth, and blurred vision, are not commonly seen with the SSRIs.
Because they have fewer adverse effects and are relatively safe even in overdose, the SSRIs have largely replaced TCAs and MAO inhibitors as the drugs of choice in treating depression. SSRIs are the most common antidepressants in clinical use. They are: fluoxetine (the prototype), citalopram, escitalopram, fluvoxamine, paroxetine and sertraline. Escitalopram is the S-enantiomer of citalopram.
ACTIONS
- 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.
- Antidepressants, including SSRIs, typically take at least 2 weeks to produce significant improvement in mood, and maximum benefit may require up to 12 weeks or more.
USES
The primary indication for SSRIs is depression.
A number of other psychiatric disorders also respond favorably to SSRIs, including obsessive-compulsive disorder, panic disorder, generalized anxiety disorder, posttraumatic stress disorder, social anxiety disorder, premenstrual dysphoric disorder, and bulimia nervosa.
SSRIs are usually considered first line for the treatment of premature ejaculation.
Nefazodone and Trazodone
5HT2 ANTAGONIST/REUPTAKE INHIBITORS (SARIs)
NEFAZODONE and TRAZODONE
When 5-HT reuptake is blocked by SSRIs, all 5-HT receptors are stimulated by an increase in 5-HT. Stimulation of 5-HT1A receptors in raphe may help depression. But stimulation of 5-HT2 receptors in forebrain may cause agitation or anxiety, and stimulation of 5-HT2 receptors in spinal cord may cause sexual dysfunction. Thus, an agent that combines 5-HT reuptake blockade with 5-HT2 antagonism would theoretically decrease undesired actions of 5-HT stimulating 5-HT2 receptors.
The main action of both nefazodone and trazodone appears to be blockade of the 5-HT2A receptor. Inhibition of this receptor is associated with substantial antianxiety, antipsychotic, and antidepressant effects.
Nefazodone is a weak inhibitor of SERT and NET and a potent antagonist of postsynaptic 5-HT2A. Nefazodone has been associated with hepatotoxicity. Nefazodone is no longer commonly prescribed.
Trazodone is a weak but selective inhibitor of SERT. Its primary metabolite is a potent 5- HT2 antagonist. Trazodone also blocks α1and H1 receptors. Extremely sedating. Excellent hypnotic. The most common use of trazodone in current practice is as an unlabeled hypnotic. Rare but troublesome adverse effect: priapism.
DRUG INTERACTIONS
Nefazodone is an inhibitor of CYP3A4.
Trazodone is a substrate but not a potent inhibitor of CYP3A4.
Amitriptyline and Nortriptyline
TRICYCLIC ANTIDEPRESSANTS (TCAs)
Pregnancy
PREGNANCY
Lithium use during pregnancy has been associated with congenital cardiac abnormalities.
Valproate taken during pregnancy can cause major teratogenic effects. Unless there is no alternative it should not be used during pregnancy.
Carbamazepine is not recommended for use during pregnancy unless no alternatives exist, due to increased risk of major malformations.
