Treatment for Depression, other syndromes and Lithium

Question 1

Moving on to the next class of Anti-Depressant drugs are the 5-HT antagonist/reuptake inhibitors (SARIs). Nefazodone and Trazodone. What are the features of these two drugs?

Answer 1

Blockade of the 5-HT2A receptor

–associated with substantial anti-anxiety, anti-psychotic and anti-depressant effects

Question 2

What are features of Nefazodone (SARIs)?

Answer 2

Weak inhibitors of SERT and NET

• -potent antagonist of postsynaptic 5-HT2a
• –associated with hepatotoxicity therefore no longer commonly prescribed

Question 3

What are features of Trazodone (SARIs)?

Answer 3

Selective inhibitor of SERT
—metabolite is a potent 5-HT2 antagonist
–also blocks alpha 1 and H1 receptors
–extremely sedating
–excellent hypnotic (Therefore this is the most common use of the drug)
AE: priapism

Question 4

What are drug interactions with Nefazodone and Trazodone?

Answer 4

Nefazodone: inhibitor of CYP3A4
Trazodone: substrate but not a potent inhibitor of CYP3A4

Question 5

The last category of drugs for Anti-Depressants are the NASSA (Noradrenergic and Specific Serotonergic Antidepressants). The drug is Mirtazapine. What are some features?

Answer 5

Mirtazapine

• -potent antagonist of central presynaptic alpha 2 adrenergic receptors, and thus enhances release of NE and 5-HT
• -potent H1 antagonist, which is associated with sedation and weight gain
• -useful in insomnia or agitation

Question 6

What are your choices of drugs for depression?

Answer 6

SSRI: initial treatment of choice
–choice between them comes down to cost and drug interactions
Fluoxetine: reasonable first choice for adults or children not taking other drugs that may interact with it
Citalopram or Sertraline: reasonable first choice for adults taking other drugs that interact with Fluoxetine

Question 7

Augmentation with an atypical anti-pyschotic agent may be helpful when the response to anti-depressant agents is inadequate, what are these drugs?

Answer 7

Quetiapine, Aripiprazole and Olanzapine

Question 8

After major depression, anxiety disorders are the most common application of anti-depressants. What drugs should be used?

Answer 8

SSRI
–generalized anxiety disorder, social anxiety disorder, PTSD, panic disorder and OCD
Bupropion:
–less effective than other anti-depressants for tx of anxiety

Question 9

TCAs are used in the treatment of neuropathic and other pain conditions. What drugs are generally useful in treating pain disorders?

Answer 9

Drugs that possess both NE and 5-HT reuptake blocking properties
–duloxetine: diabetic neuropathy and fibromyalgia
SSRIs are not effective for chronic pain

Question 10

What drugs are used for eating disorders, premenstrual dysphoric disorder and smoking cessation?

Answer 10

Eating Disorder
–anti-depressants are used for bulimia (Fluoxetine)
PMDD
–SSRIs (Fluoxetine and Sertraline)
Smoking Cessation:
–Bupropion (appears to be as effective as nicotine patches)

Question 11

A major depressive episode may be the initial presentation of bipolar disorder. Treating such an episode with an anti-depressant alone may precipitate what?

Answer 11

Mania

• -in patients with bipolar disorder and is therefore not recommended
• -patients should therefore be screened for bipolar before starting anti-depressant therapy

Question 12

Moving on to drugs for Bipolar Disorder. The main drug is Lithium. What are some feature of this drug?

Answer 12

Lithium:
–standard treatment for bipolar disorder
–tx: manic-depressive patients and in tx of manic episodes
–effective in 60-80% with mania and hypomania
Narrow therapeutic window due to toxic effects

Question 13

What is the MOA for Lithium?

Answer 13

Inositol Depletion Theory:

• -G protein linked receptors which couple to Gq activate phospholipase C ,cleaves PIP2 to yield DAG and IP3
• -IP3 is signaling is terminated by conversion to IP2 and by IP3 phosphatase. IP2 is converted to IP1 by inositol polyphosphatase and IP1 is then converted to free inositol by inositol monophosphate
• -lithium blocks 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 siganling cascade in the brain

Question 14

Inhibition by lithium is uncompetitive, therefore only neurons with what?

Answer 14

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
• -no idea which neurotransmitter is involved

Question 15

What are the PK for lithium?

Answer 15

Given by mouth as a carbonate salt
–absorbed rapidly and completely from the gut
Half life is 20h
Plasma Levels need to be monitored

Question 16

Acute lithium toxicity results in various neurological effects, progressing from confusion and motor impairment, to coma, convulsions and death if plasma concentrations reaches 3-5mM. What are some main adverse effects?

Answer 16

1. Tremor: propranolol and atenolol can alleviate this
2. Seizure
3. Hypothyroidism
4. Nephrogenic Diabetes Insipidus: administer lithium with amiloride. other options are Thiazides and NSAIDs
5. Acute intoxication is characterized by vomiting, profuse diarrhea, coarse tremor, ataxia, coma and convulsions
6. Use of lithium during pregnancy may increase the incidence of congenital cardiac anomalies.

Question 17

What is the monitoring and drug interactions for lithium?

Answer 17

Monitoring: serum lithium concentrations and thyroid and renal function
Drug Interactions:
–renal clearance of lithium is reduced by diuretics
–NSAIDs can facilitate renal proximal tubule resorption of lithium and thereby increase lithium serum concentrations
–ACEI and ARBs cause lithium retention

Question 18

What are some alternatives for lithium?

Answer 18

1. Valproate and Carbamazepine
2. Atypical Antipsychotics: Olanzapine and Aripiprazole are approved for maintenance treatment
3. Atypical Antipsychotics: Quetiapine and Risperidone are approved for acute mania or mixed episodes
4. Combo of Olanzapine with Fluoxetine in depression + bipolar
5. Lamotrigine is approved for maintenance treatment
6. Liver function and CBC should be monitored in patients taking valproic acid

Question 19

What drugs are not used in bipolar and pregnancy?

Answer 19

1. Lithium has been associated with congenital cardiac abnormalities
2. Valproate taken during pregnancy can cause major teratogenic effects
3. Carbamazepine is not recommended