Drugs- Mood Stabilizing Drugs and other treatments for Bipolar Disorder (Martin)

Question 1

DSM diagnostic criteria for manic episode

Answer 1

A. A distinct period of abnormally and persistently elevated, expansive, or irritable mood and abnormally and persistently increased activity or energy, lasting at least one week and present most of the day, nearly every day (or any duration if hospitalization is necessary).

B) must meet 3 of the following (DIG FAST)
-Distractability
-irresponsibility - hedonistic- doesn’t care about consequences
(sexual indiscretion, foolish)
-grandiosity - inflated self esteem
-Flight of ideas
-Activity (increase in goal directed activity or agitation
-decreased need for sleep
-talkativeness

C) impairs social or occupational functioning or may necessitate hospitalization

D) not attributable to substance or other medical condition

Question 2

what is the standard of treatment for bipolar disorder

Answer 2

lithium

but antiepileptic drugs such as valproate and carbamazepine are also widely used despite evidence that they are less effective in preventing recurrence.

Question 3

treatment of acute mania or mixed episodes and maintenance of bipolar disorder

Answer 3

atypical or second generation antipsychotic drugs

Question 4

treatment of depression associated with bipolar disorder

Answer 4

quetiapine
lurasidone

combo of olanzapine with fluoxetine

many studies have shown that lithium has protective effects against suicide and self-harm.

Question 5

prevention of recurrent depression in bipolar disorder

Answer 5

lamotrigine (anticonvulsant)

Question 6

MOA of lithium

Answer 6

Lithium is believed to attenuate signaling via receptors coupled to the phosphatidylinositol bisphosphonate (PIP2) second messenger pathway (see figure below). Lithium interferes with the resynthesis of PIP2, leading to its relative depletion in neuronal membranes of the CNS. PIP2 levels in peripheral membranes are unaffected by lithium. Thus, lithium disrupts the IP3/DAG intracellular signaling pathway. Lithium is also known to inhibit glycogen synthase kinase-3 (GSK-3) a kinase that pays a role in several different intracellular signaling pathways. Additional effects on adenylyl cyclase activity, G proteins, and protein kinase C activity have been described but the relevance of all these findings is not clear. Li+ substitutes for Na+ ion in generating action potentials and in Na+-Na+ exchange across membranes but does not affect Na+-Ca++ exchange or the Na+,K+ ATPase pump.

Question 7

Both lithium and valproate may take days to weeks to have a full therapeutic effect; acutely manic patients often require what?

Answer 7

an antipsychotic drug or additional temporary treatment with a benzodiazepine.

Antidepressants should be tapered and discontinued during a manic episode.

Question 8

which drugs decreases the risk of recurrent manic and depressive episodes.

Answer 8

lithium alone OR in combo with valproate, carbamazepine, or lamotrigine

Question 9

what should you do before starting lithium

what about when you want to stop lithium

Answer 9

kidney function tests

• creatinine
• urine specific gravity

thyroid function tests

repeat kidney function tests every 1-2 times per year

• Rapid discontinuation of lithium increases the risk of relapse and possibly suicide, so lithium may need to be tapered slowly over 3 months if it is to be discontinued after long-term maintenance.

Question 10

signs of lithium toxicity

Answer 10

tremor dysarthria, delirium, coma, seizures, and autonomic instability.

Question 11

what causes increased reabsorption of lithium

Answer 11

• Volume depletion or renal impairment from any cause increases lithium reabsorption. Examples of such conditions include gastrointestinal losses, acute decompensated heart failure, cirrhosis, and the administration of diuretics, NSAIDs, or angiotensin converting enzyme inhibitors.

Question 12

ADR’s of lithium

Answer 12

LMNOP

M movement- tremor- add B- blocker (propranolol)
N- nephrogenic diabetes insipidus *polyuria
O-hypOthyroidism- goiter, can cause acute exacerbations of bipolar illness
P-pregnancy problem

Nausea and fatigue may occur in the first days to weeks of treatment with lithium, even when serum concentrations are in the recommended range. Tremor, thirst, polyuria, edema and weight gain may persist for the duration of treatment.

Question 13

what substances can decrease the concentration of lithium

Answer 13

caffeine

theophylline

Question 14

Lithium contraindications

Answer 14

Lithium use during pregnancy has been associated with congenital cardiac abnormalities. High neonatal lithium concentrations are a risk factor for lower Apgar scores, longer hospital stays, and reversible neurologic toxicity that could be minimized or avoided by withholding maternal lithium for 24 hours before delivery.

Question 15

what are the three types of lithium toxicity (poisoning) that can occur

Answer 15

Lithium poisoning may be (1) acute, as occurs when a patient who is not on lithium therapy ingests a bottle of lithium tablets in a suicide attempt; (2) acute-on-chronic, as occurs when a patient who is on lithium therapy also ingests a large number of lithium tablets all at once; or (3) chronic, as occurs when a patient on a stable lithium regimen suffers a reduction in renal function.

Question 16

monitoring of lithium levels?

Answer 16

Use of lithium requires monitoring to maintain serum concentrations within the therapeutic range and avoid toxicity. Lithium has a very narrow therapeutic index (~2). Concentrations should be measured about 12 hours after the last dose. For acute treatment, target serum concentrations are 0.8 to 1.0 mEq/L. For maintenance, serum concentrations should be between 0.6 and 1.2 mEq/L. Renal function and thyroid function should be monitored routinely in patients taking lithium. Usually an initial assay of lithium serum concentration is performed at about 5 days after beginning therapy with lithium, i.e., after a steady-state serum concentration has been obtained. This process of determining plasma levels should be repeated anytime a dosage change occurs. Plasma lithium levels should be routinely monitored until predictable and effective levels of the drug have been established and then monitoring at longer intervals can be employed.

Question 17

what is divalproex

Answer 17

valproic acid and sodium valporate

Question 18

what pt’s is valproate best used in

Answer 18

best for patients with mixed episodes or for patients with rapid-cycling bipolar disorder

Valproate seems to be more effective for treating manic episodes than depressive episodes

Valproate may also be more effective in preventing manic relapses than in preventing depressive episodes.

Question 19

MOA of valproate

Answer 19

The proposed mechanism of action for valproate include blockade of voltage-dependent sodium channels, increased GABA levels via blockade of GABA transaminase, and inhibition of T-type calcium currents.

Question 20

ADRs of valproate

Answer 20

sedation
weight gain
GI upset

monitor liver function due to elevation in hepatic transaminases

hair loss

CI in pregnancy - neural tube defects

thrombocytopenia

increases polycystic ovarian syndrome in women up to nine fold

Question 21

carbamazepine

MOA and use

Answer 21

• Carbamazepine is approved for the treatment of bipolar disorder. It is not as useful for patients who do not wish to or cannot comply with blood testing and close monitoring. It can be used in combination with lithium, valproate, or atypical antipsychotics.

MOA:These drugs reduce the propagation of abnormal impulses in the brain by blocking reactivation of voltage-dependent sodium channels,

induction of cytochrome P450’s

Question 22

ADR’s of carbamazepine

Answer 22

rash
dizziness, diplopia
nausea, headache, somnolence
hyponatremia

Rare and serious:
aplastic anemia, agranulocytosis, SJS

continuously monitor blood counts

CI in pregnancy

Question 23

Lamotrigine MOA

Answer 23

• Lamotrigine is FDA-approved for the maintenance treatment of bipolar disorder.
• Lamotrigine blocks sodium channels as well as high voltage-dependent calcium channels.

Question 24

ADR’s of lamotrigine

Answer 24

dizziness and ataxia

somnolence, headache

diplopia, nausea, vomiting

rash

insomnia

About 10% of patients develop mild rash; severe, life-threatening rash, including Stevens-Johnson syndrome and toxic epidermal necrolysis, has occurred rarely.

Question 25

what causes decreased concentration of lamotrigine

Answer 25

Oral contraceptives

Question 26

use of lithium during pregnancy

Answer 26

• Lithium use during pregnancy has been associated with congenital cardiac abnormalities. High neonatal lithium concentrations are a risk factor for lower Apgar scores, longer hospital stays, and reversible neurologic toxicity that could be minimized or avoided by withholding maternal lithium for 24 hours before delivery.

Question 27

valproate and pregnancy

Answer 27

• Valproate taken during pregnancy can cause neural tube defects, cardiac and other major teratogenic effects, adverse effects on neurocognitive development and neonatal toxicity; unless there is no alternative, it should not be used.

Question 28

carbamazepine during pregnancy

Answer 28

is not recommended for use during pregnancy unless no alternatives exist, due to increased risk of major malformations including neural tube defects, low birth weight, and fetal and neonatal vitamin K deficiency, which can lead to neonatal hemorrhage.

Question 29

lamotrigine in pregnancy

Answer 29

use in pregnancy has produced inconsistent data; it appears to have a lower risk of adverse fetal outcomes than valproate or carbamazepine, but midline clefts have been reported.

Question 30

what are the use of second generation antipsychotics

Answer 30

mania in bipolar disorder

• Second-generation antipsychotics are generally added on to therapy with either lithium or valproate.
• Antipsychotics appear to be more consistently effective than antidepressants in the treatment of depression of bipolar disorder and also do not increase the risk of inducing mania or increasing the frequency of bipolar cycling

Question 31

what occurs with monotherapy using antidepressants in bipolar disorder

Answer 31

Monotherapy with antidepressant drugs can precipitate mania in patients with bipolar disorder.

Question 32

is bipolar disease genetically linked?

Answer 32

yes!
first degree relative 24 times more likely to develop bipolar disorder

avg age of onset is age 21, however first symptoms can show up in teens

Question 33

MOA of lithium

Answer 33

inhibits phosphatase enzyme primarily responsible for conversion of IP2 to IP1 and IP1 t inositol

depletion of PIP2 with chronic use of lithium –> PIP2 is the source of second messangers IP3 and DAG

depletion of PIP2 –> lead to decreased responsiveness to synaptic transmission for those receptors which utilize Phosphoinositide second messenger signalling

takes 2-3 weeks to start working

Question 34

effects of hydration status on lithium

Answer 34

dehydration –> can lead to toxic levels quickly of lithium due to increased plasma concentrations and decreased renal excretion

20-40 % of bipolar pt’s do NOT respond to lithium

Question 35

acute plasma drug level?
maintenance?
toxic levels?

Answer 35

acute- 1 - 1.5

maintenance - 0.6- 1.2

toxic - 2.0

Question 36

effects of valproic acid on lamotrigine

Answer 36

doubles conc

Question 37

effects of carbamazepine on lamotrigine

Answer 37

halves