ANTIDEPRESSANTS

I. Antidepressants are prescribed specifically for affective disorders that
are characterized by extreme depression (dysphoria), extreme elation (mania),
or both. Monopolar depression may affect 15% of all adults during any given
year of their lifetime. Treatment usually takes 2-4 weeks and leads to 85%
remission.

II. Affective disorders such as depression are thought to result from a
chemical imbalance between three neurotransmitters - norepinephrine, serotonin
and perhaps dopamine. More recent research has suggested that beta-adrenergic
receptors may be involved.

III. As a class of drugs, antidepressants are generally:

• orally administered (i.m. administration very infrequent and limited to
  

  specific drugs)
  

  
  
• 90-95% bound to plasma proteins
  
  
• metabolized by the liver, with metabolites excreted in urine
  
  
• drugs with long “half-lives” (e.g., imipramine - t½=24 hours)
  
  
• drugs with a relatively small therapeutic index
  
  

IV. There are at least four prominent classes of antidepressant drugs:

1. Tricyclics - the tricyclics attempt to remedy depression by inactivating the “amine” pump on the presynaptic nerve terminal and thus limiting the reuptake of both norepinephrine and serotonin. Unfortunately, many also have effects at muscarinic receptors, histamine type-1 receptors and alpha-1 receptors. There are two general types of tricyclics:
   
   

1. Tertiary Amine Tricyclics:
   
   

1. amitryptyline (“Elavil” - can be given i.m.)
   

   
   
2. clomipramine (“Anafranil”- usually given for obsessive-compulsive disorder (OCD); not very selective, can cause seizures)
   
   
3. doxepin (“Sinequan” - increased sedation, but absence of cardiovascular side effects)
   
   
4. imipramine (“Tofranil”- can be given i.m. and pamoate formulation also available)
   
   
5. trimipramine (“Surmontil” - very sedating and moderately anticholinergic)
   

2. Secondary Amine Tricyclics:
   

   
   

1. amoxapine (“Asendin” - a dibenzodiazepine that is a metabolite of the antipsychotic loxapine; therefore, it has a dopaminergic as well as adrenergic component)
   
   
2. desipramine (“Norpram” - naturally occurring metabolite of imipramine)
   
3. maprotiline (“Ludiomil” – very new with increased potential for seizures)
   
   
4. nortryptyline (“Pamelor” - metabolite of amitryptyline; indicated for elderly patients)
   
   
5. protryptyline (“Vivactil” - lacks sedative prop.; indicated for “sleepy” depressives)
   
   

2. Selective Serotonin Reuptake Inhibitors (SSRI’s):
   
   

1. citalopram (“Celexa”)
   
   
2. fluoxetine (“Prozac”; t_1/2=72 hr.)
   
   
3. fluvoxamine (“Luvox”)
   
   
4. paroxetine (“Paxil” – noted for its anticholinergic side effects; recently approved for social phobia)
   
   
5. sertraline (“Zoloft”; t_1/2=36 hr.)
   
   
6. venlafaxine (“Effexor” – a phenethylamine that has been shown to produce withdrawal following chronic treatment and rebound effects)
   
   

2. Monoamine Oxidase Inhibitors (MAOI’s) - MAO inhibitors, which are usually
   used only to treat refractory depression, attempt to remedy this by
   inactivating the enzyme (MAO) that metabolizes norepinephrine and
   serotonin.
   

   
   

1. isocarboxazid (“Marplan”)
   
   
2. phenelzine (“Nardil”)
   
   

3. tranylcypromine (“Parnate”)
   
   

D. Atypical:

1. bupropion (“Wellbutrin” or “Zyban” – known for its ability to block the reuptake of dopamine, and possibly norepinephrine; increased incidence of seizures noteworthy)
   
   
2. mirtazapine (“Remeron” – sedation is one of its most prominent adverse effects)
   
   
3. nefazodone (“Serzone” - prominent effects are through serotonergic mechanisms)
   
   
4. trazadone (“Desyrel” - virtual absence of cardiac and anticholinergic side effects owing to its prominent serotonergic properties; priapism has been reported)
   

V. Of the adverse effects that can occur from taking antidepressants, sedation
is the largest initial problem.

A. There are also a host of other problems that can occur while taking
antidepressants:

2. cardiovascular effects are some of the most serious side effects.
3. orthostatic hypotension can lead to tachycardia
4. antimuscarinic effects at the sinoatrial node can unmask sympathetic influences
5. seizures - many antidepressants lower the seizure threshold
6. blood abnormalities - although agranulocytosis is rare, these drugs can cause bone marrow depression, thrombocytopenia or eosinophilia.
   

B. Drug interactions are also of considerable concern.

1. Antidepressants should not be given with other CNS depressants, any antimuscarinic agent, or a MAO inhibitor.
   
2. Interactions with various sympathomimetic agents is very problematic:
   

1. indirect-acting sympathomimetics:
   

1. amphetamine
   
   
2. tyramine (dietary sources of tyramine are particularly a problem)
   
   

2. mixed-acting sympathomimetics (often found OTC):
   

1. pseudoephedrine
   
   
2. phenylpropanolamine

Bipolar Depression:

1. The most common treatment for bipolar depression is lithium, although other treatments are available (e.g., Valproic Acid - “Depakote” or the anticonvulsant carbamazepine – “Tegretol”). Lithium can also be given in combination with certain antipsychotics to treat psychosis-induced mania. Characteristically, lithium is:
   

• orally administered and absorbed, although its passage into the CNS is slow (its kinetics are similar to that of the sodium ion (Na⁺))
• excreted 95% unchanged in urine; does not bind to plasma proteins
  
• long acting (i.e., t½=24 hours)
  
• ineffective in approximately 30% of the patients who take it
  

2. The mechanism of action for lithium has not been firmly established, although we do know that it inhibits nerve metabolism, alters reuptake of serotonin, norepinephrine and dopamine, and decreases release. We also know that it directly affects neuronal inositol levels.
   

3. The side effects produced by lithium frequently cause a problem with compliance. This is particularly difficult with lithium since the therapeutic dose is very near the toxic dose. In general, lithium produces:
   

1. problems with the GI tract – can be an indication of toxicity or simply peak absorption
   

1. nausea
2. diarrhea

2. drowsiness
   
   
3. polyuria – 80% of filtered Li+ is reabsorbed by the proximal renal tubules
   
4. dry mouth and thirst
   
5. weight gain
   
6. insomnia
   
7. a small number of patients develop a benign, diffuse, nontender thyroid enlargement, suggestive of thyroid dysfunction
   
8. a benign, sustained increase in circulating polymorphonuclear leukocytes occurs during chronic treatment and is reversed within a week of terminating treatment
   

4. Effects of Acute Li+ Intoxication
   

1. vomiting
   
   
2. profuse diarrhea
   
   
3. coarse tremor ataxia
   
   
4. coma
   
   
5. convulsions – in nonepileptic patients at therapeutic doses
   
   

5. Drug interactions:
   

1. Diuretics seem to be the most problematic interaction because most diuretics will increase sodium excretion and indirectly decrease lithium excretion. This, in turn, leads to increased or toxic levels of lithium.
2. increase excretion – osmotic diuretics and acetazolamide
   
   
3. decrease excretion – the thiazides and other diuretics that deplete sodium
   
   

B. nonsteroidal antiinflammatory agents such as indomethacin, naproxen and
ibuprofen may diminish clearance and increase plasma Li⁺

Category: Pharmacology Notes