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• National Association for the Mentally Ill—http://www. nami.org/

• National Institutes for Mental Health, Bipolar Disorderhttp://www.nimh.nih.gov/ healthinformation/bipolarmenu.cfm

Pharmacologic Therapy

® Pharmacotherapy is the cornerstone of acute and maintenance treatment of bipolar disorder. Mood stabilizing drugs are first-line treatments and include lithium, DVP, carbamazepine, and lamotrigine. Atypical antipsychotics other than clozapine and paliperidone are also approved for treatment of acute mania. Lithium, lamotrigine, aripiprazole, olanzapine, and quetiapine are approved for maintenance therapy. Quetiapine's maintenance therapy indication is adjunctive with lithium or DVP. Drugs used with less research support and without FDA approval include topiramate and ox-carbazepine. Benzodiazepines are used adjunctively for mania.

® Mood stabilizing drugs are the primary treatment for bipolar depression. Among antipsychotic drugs, quetiapine as monotherapy and olanzapine in combination with fluoxetine are approved for bipolar depression. Antidepressants can be used, but usually along with a mood stabilizing agent to prevent a mood switch to mania and after the patient has failed to respond adequately to optimal mood stabilizing ther-21

apy Combinations of two mood stabilizing drugs or a mood stabilizing drug and either an antipsychotic or antidepressant drug are common, especially in acute mood episodes.

Mood stabilizer drugs are considered the primary pharmacotherapy for relapse prevention, and they are often combined with antipsychotic drugs. Aripiprazole, olanzapine, and quetiapine are approved for maintenance therapy.

Table 39-4 includes a summary of current drug therapy for bipolar disorder. An algorithm for treatment of bipolar mania is shown in Table 39_2.

Mood Stabilizing Drugs

The ideal mood stabilizing drug has four desired effects: treatment of acute mania, treatment of acute bipolar depression, prevention of manic relapse, and prevention of bipolar depression relapse. All currently approved mood stabilizing drugs have demonstrated efficacy over placebo for one or more of these effects, but there are differences among them with regard to specific patient populations. Choice of treatment is dictated by individual patient characteristics and history. Few studies have compared mood stabilizing drugs to each other in systematic clinical trials. Effect sizes across placebo-controlled trials of individual agents are generally similar. Lithium is often considered the first-choice drug for the classic presentation of bipolar disorder. Treatment of childhood bipolar disorder is less well researched. Lithium is FDA approved in children and adolescents as young as age 12. Among antipsychotic drugs, aripiprazole and risperidone are FDA approved in children and adolescents as young as age 10. Treatment of bipolar disorder during pregnancy and during breast-feeding is a challenge because of the risks of drug exposure in utero and transmission of drugs via breast milk.

Lithium

Lithium was the first approved mood stabilizing drug. It remains a first-line agent and sets the standard for efficacy against which other drugs are usually measured. It has antimanic efficacy,2p2revents bipolar disorder relapse, and more modest efficacy for bipolar depression.2 It remains the only drug classified as a mood stabilizer that is supported by multiple controlled trials in mania, depression, and relapse prevention.

In most studies, lithium's efficacy is equivalent to that of the anticonvulsant mood sta-

bilizers and the atypical antipsychotic drugs. It is most effective for patients with few previous episodes, symptom-free interepisode remission, and a family history of bipolar disorder with good response to lithium. Patients with rapid cycling bipolar disorder are less responsive to lithium, however, than to other mood stabilizing drugs 24

such as DVP. Additionally, its efficacy for bipolar depression is less robust than for mania.25 It may also be less effective in patients with mixed mood episodes (symp toms of mania and depression occurring simultaneously) and in mania secondary to nonpsychiatric illness.

Table 39-4 Product Formulation, Dose, and Clinical Use of Agents Used in the Treatment of Bipolar Disorder fiwe'lt lirifl

B-rjnU

Clinical U«

Lilhiuni Sail!

FDA approved iat use In bipolar JiiOrdti

UttHum tarbofiau! [iluinh CjpwjK.^ 505 ng.

I lElnuin L in,nf

Eskalith Cfl Lilhobkt i^erttik

FS laHk.-'M'tiO irifl Efl lablet: 300 mg

Capiuk- ISO. 300,

WOnvj ¿00mif/hima, Clmfq or prtmol pii 5 ml]

900 i.400 rng/Ujiy In 2 ■! divided iJt»ev pn'fpiafilyttiHi iiwah. Iliete is wide vixialion in (he dosage needed Lo achieve itaiwaiHc rnpsnse 0"td iz-IKJUI niu(fi hi hium «jncenddfion 1ije„ -1.2 mEij/t (ninvii/u for riwin:enancif ine^R/ fU t_1 5 mfiVI Oimiol'L) fa acuie nriooilfptjad« UkLn li huuri jflti Ids! dcnel Single daily d(><ir*j Is iff«(Kii- iird wtii« liiwei (ifrtil eifecti

MunuLhefipy t* In rnnibination wjlh otli« diugs lor Hv.1 acute IrHtmtM ofnfyjnid ind foi maintenance I'eatrnem

AntiCOnvul xnnf »

FDA approved fur uie In bipolar diioKlei

(.■ifhanidjeplne E<(ustro Capiule 100 nnj. iflO Star! it 100-290 nig twk? a Incrate ty Mcnol hefapy ca in

Tegierol Tr^ctul XK tai battel mgt 300 mg Sfl; may Open CiflSulC tXJl. moi crush or chew beidt: I jkt' with ftxxJ UilcC200niQ Chewafcta uMcc lffll rnq Suspension. 100nq/5 ml EflOtteCl0Q20ft«Mmfl Ell rapjule: JOQ rinfj

200 mg every 3-i days JCW-l^eoo irKf/tliy irt ^ if.dMdeddCKH. Tatget serum concentiation ts t-l? mcgvinL 07-si combination wilholht* rinpji for |hi acuW treatment of mania or mined Ipisgdt; ft* bipoljf I disorder

DVP sodium

VPA syrup

Lamotrigine

Depakote.

generic Depakote ER

Depakene, generic Depakene, genetic tamlcial

Enteric-coiled. delayed- 750-3.000 my/day (20 60 mg/kg/day) in 2-3 release tablet: 125. divided doses for delayed-release DVP or 250.500 Tig VPA

Sprinkle ca»uie: 125 mg ER DVP may be given once daily £R tablet: ;50,500 mg A loading dose of 20-30 mg/kg/day can be grven, then 20 mg/kg/day <wj titrated to a serum concentration of 50-125 mcg/mt (347-866 pmoJes/l)

Tablet: 25,100.150,

200 mg Chewabtetablet* 2.5.

25 mg Orally disintegrating tablet: 2% 50.100. 200 mq

50-400 mg/day in divided doses. Dosage should be slowly increased by (blowing describing information. if ()VP is added to lamotrigine. the lamotrigine dosage should be reduced by half

Monotherapy or in combination with other drugs for the acute treatment of mania. Although commonly used for relapse prevention, maintenance treatment is not FDA approved

Monotherapy or in combination with other drugs for the long-term maintenance treatment of bipolar depression

Anticonvulsants and Other Drugs Not FDA Approv»d for Us« in Bipolar Disord«r

Clonazepam Klonopin, Tablet: 0.S, 1.2 mg torazepam

Oxcarbazepine

Topiramate generic

Atrvan generic

Trileptal generic

Topamax

Tablet: 0.5.1.2 mg Oral solution: 2 mg/mt Injection: X 4 mg/ml

Tablet: ISO 300.

600 mg Suspension 300 mg/ SmL

Tablet: 25.100.200 mg Sprite capsule: 15. 2Smg

0.5-20 mg/day In drvided doses or one dose at bedtime Dotage should lx- slowly adjusted up and dewn according to response and adverse effects

2-10 mg/day in divided doses or one dose at bedtime

Dosage should be slowly adjusted up and down according to response and adverse effects

300-1,200 mg/day in two drvided doses Doses should be slowly adjusted up and down according to response and adverse effects (ejg, 1S0-300 mg twice daily and increase by 300-600 mg/day at weekly intervals) 50-200 mg/day in divided doses Dosage should be slowly increased to minimize adverse effects (e.g. 25 mg at bedtime for 1 week, then 25-50 mg/day increments at weekly intervals

Use in combination with other drugs for the acute treat mint of mania or mixed eprsodes. Use as a short-term adiunctive sedative hypnotic agent

May cause fewer adverse drug-drug interactions than carbamazepine, but causes more G side effects and hyponatremia. Evidence is limited regarding efficacy Not recommended for the acute treatment of mania or mixed episodes due to lack of efficacy; used as an adjunctive agent with established mood stabilizers

Atypical Antipsychotics

FDA approved for bpolar disorder

Aripiprazole

Olanzapine

Ability AbBfy

Disc melt

Zyprexa Zyprexa Zydis

Tablet 2,5 ia 15,20.

30 mg Oral solution: Smg/Snl Tablet, oraly disintegrating:10. IS mg Tablet: 2-5,5.7.5.10.

15.20 ma Tablet, oraly disintegrating: 5.10. 15.20 mg

10-30 mg/day once daty

5-20 mg/day in one oi two doses

Used as monotherapy- or in corrfc«natcn with Sthum or valproate for the acute treatment of nwia or mixed states for bipolar I disorder and prevention of rrwnic relapse

Used as monotherapy or in COmb»\)tion with lithun or valproate for acute treatment of mania ex mixed states for bipolar I drvxder and prevention of manic relapse. Used in comtoration with fluoxetine (CfO for treatment of bipobi depression

JPO. 4® rny tfl i^bW: M. 15Ü, JOfl 500,400 mil tombiriol ¡un YY¡[ti Idhum üi iw for .■iruteiri'.imn'iii oí nynü, ríiÍMíd ítalri foi tripolar l tjiíordef, iirvd depressron of bipolar I and tjipcUr II CfiíOr-dei. Ustít ídUJKtHníly Vi 11) lithium II-DvPfof ielapHíp<Qvent¡on of t"p0«3f rivrlií ¿rd depresión

JPO. 4® rny tfl i^bW: M. 15Ü, JOfl 500,400 mil tombiriol ¡un YY¡[ti Idhum üi iw for .■iruteiri'.imn'iii oí nynü, ríiÍMíd ítalri foi tripolar l tjiíordef, iirvd depressron of bipolar I and tjipcUr II CfiíOr-dei. Ustít ídUJKtHníly Vi 11) lithium II-DvPfof ielapHíp<Qvent¡on of t"p0«3f rivrlií ¿rd depresión

Ifcod IS or

«dRiKCiveV ^(h iiriiiiini or DvP for «ute irania or misis) yyisxJn cí bíjolin I

divJKln

BÍSÍV kkjrit nacrMphíiK ¡%nd( FtM Íf5f¥0iíl?d ÍOf bipolar

Füspwidonc RspcrcM Tablet: <Í25Í.(15| 1,2,3, 0.5 fr nsy/üay in one or tvra dosci iji'IH'IÍ; 4 mg

Risperdal Oral solution: I mg/hiL

Risperdal disintegrating: (ti i.

Consta mg

Loníj-saini) InjeciíHH?-IJ.Í, î5, ÏÏ.S. SO mg

Zip<asidonif Gucdon CapsuVi JO. 40, tO. BO 40-160 mg/day in divided dows mg

Ihcd os monotherapy or lu lin il il 0c

DvP for acule mania or mxed episode of bipolar l disoidc

VPA* Valproic Kid: DVP. divalproex From Reft. 2313.30,33. Î4 36,4M1

Evidence shows lithium's effect on suicidal behavior is superior to that of other mood stabilizing drugs.26 Lithium reduces the risk of deliberate self-harm or suicide by about 70%.

Mechanism of Action. Lithium's pharmacologic mechanism of action is not well understood and involves multiple effects. Possibilities include altered ion transport, effects on neurotransmitter signaling, blocking adenyl cyclase systems, effects on inositol, neuroprotection or increased BDNF, and inhibition of second messenger sys-

tems

Dosing and Monitoring. Lithium is usually initiated at a dosage of 600 to 900 mg/day. Although it is most commonly given in a divided dosage, once-daily dosing is acceptable, especially with sustained-release formulations, and once-daily dosing can improve patient adherence and reduce some side effects. Lithium has a narrow therapeutic index, meaning the toxic dosage is not much greater than the therapeutic dosage. Lithium requires regular serum concentration monitoring as a guide to dosage titration and to minimize adverse effects. At least weekly monitoring is recommended until the patient is stabilized, then the frequency can be decreased. Well-maintained patients who tolerate lithium without difficulty can be monitored by serum concentration as infrequently as twice yearly. Dosage is titrated to achieve a serum lithium concentration of 0.6 to 1.4 mEq/L (mmol/L). Higher serum concentrations are usually required to treat an acute episode than to prevent relapse. Serum lithium maintained above 0.8

mEq/L (mmol/L) may be more effective at preventing relapse, however, than lower serum concentrations. The suggested therapeutic serum concentration range is based on a 12-hour postdose sample collection, usually a morning trough in patients taking more than one dose per day. At least 2 weeks at a suggested therapeutic serum concentration is required for an adequate trial of lithium. Table 39-5 shows pharmacokinetic parameters and desired serum concentrations of mood stabilizing drugs used for bipolar disorder. It is common for lithium to be combined with other mood stabilizing drugs or antipsychotic drugs, if necessary, in order to achieve more complete remission of symptoms.

Adverse Effects. The most common adverse effects are GI upset, tremor, and polyuria,28 which are dose related. Nausea, dyspepsia, and diarrhea can be minimized by coadminist-ration with food, use of sustained-release formulations, and giving smaller doses more frequently to reduce the amount of drug in the GI tract at a given time. Tremor is present in up to 50% of patients. In addition to the approaches above, low-dose P-blocker therapy such as propranolol 20 to 60 mg/day often reduces the tremor.

Lithium impairs the kidney's ability to concentrate urine due to its inhibitory effect on vasopressin. This causes an increase in urine volume and urinary frequency and a consequent increase in thirst. Polyuria and polydipsia occur in up to 70% of patients. A severe form of polyuria, when urine volume exceeds 3 L/day, is known as nephrogenic lithium-induced diabetes insipidus. It can be treated with hydrochlorothiazide or amiloride. If the former is used, the lithium dosage should be reduced by 33% to 50% to account for the drug-drug interaction that could increase serum lithium concentrations and cause toxicity. Long-term lithium therapy can cause structural kidney changes such as glomerular sclerosis or tubular atrophy. Once-daily dosing of lithium is less likely to cause renal adverse effects than divided-daily dosing.

Lithium is concentrated in the thyroid gland and can impair thyroid hormone synthesis. Although goiter is uncommon, as many as 30% of patients develop at least transiently elevated thyroid stimulating hormone (TSH) values. Lithium-induced hypothyroidism is not usually an indication to discontinue the drug. Patients can be sup-

plemented with levothyroxine if continuation of lithium is desired.

Other common adverse effects include poor concentration, acneiform rash, alopecia, worsening of psoriasis, weight gain, metallic taste, and glucose dysfunction. Lithium causes ECG. Less commonly, it can cause or worsen arrhythmias. Cardiologic evaluation is recommended for patients with pre-existing cardiac disease who are can-

didates for lithium therapy. A benign leukocytosis is also common.

Lithium and other mood stabilizing drugs require baseline and routine laboratory monitoring to help determine medical appropriateness for initiation of therapy and monitoring of potential adverse effects. Guidelines for such monitoring are outlined in Table 39-6.

Acute lithium toxicity, which can occur at serum concentrations over 2 mEq/L (mmol/L), can be severe and life-threatening, necessitating emergency medical treatment. Symptoms include worsening of GI distress to include severe vomiting and diarrhea; deterioration in motor coordination including a coarse tremor, ataxia, and dysarthria; and impaired cognition. In its most severe form, seizures, cardiac arrhythmias, coma, and kidney damage have been reported. Treatment includes discontinuation of lithium, IV fluids to correct fluid and electrolyte imbalance, and osmotic diuresis or hemodialysis. In case of overdose, gastric lavage is indicated. Clinical symptoms can continue well after the serum concentration is lowered, as clearance from the CNS is slower than from the serum. Factors predisposing to lithium toxicity include fluid and sodium loss due to hot weather or exercise or drug interactions that

increase serum lithium.

Drug Interactions. Drug interactions involving lithium are common. Because lithium is not metabolized or protein bound, however, it is not associated with metabolic drug interactions that occur with other mood stabilizing drugs. Common and significant drug interactions involve thiazide diuretics, nonsteroidal anti-inflammatory drugs, and angiotensin-converting enzyme (ACE) inhibitor drugs. If a diuretic must be used with lithium and a thiazide is not required, loop diuretics such as furosemide are less likely to increase lithium retention. The ACE inhibitors can abruptly increase serum lithium with the potential of acute and fatal toxicity, even after months of no change in the serum lithium concentration. This combination is strongly discouraged.29

Table 39-5 Pharmacokinetics and Therapeutic Serum Concentrations of Lithium and Anticonvulsants Used in the Treatment of Bipolar Disorder

Lithium

Ca-bamazopin«

Oxcarbazepine DVP Sodium/VPA

Lamotrigino

CI Absorption

Regular release

Syrup/suspensiorV solution

Extended-retease/ enteric-coated tablets

Delay in absorption by food

Time to teach peak vwum concentrations

Rapid: 95-100% Sto* and erratic within 1-6 touts Faste» rate of absorption: 100% Delayed absorption: 60-90%

0.5-3 hours (regular release) 4-12 hours

(extended release) 0.25-1 hour (oral solution)

8>-90% Faster rate of absorption Deayed absorption: 8?% of the suspension; and less tlvm regular-release titolets

Stow and complete: 100%

Unknown NA

No reports of increased Unknown rote of absorption vslth fatty meals (extended release capsule)

4-5 hours (regular- 4.5 hours (range release); 1.5 l>outs oi 3-13 hours) (suspension* 3-12 haus (extended-release tablets): 41-7.7 hours (extended-release capsules): higher peak concentrations with chewable tablets

Rapid and complete (VPA)

Rapid: 98%

Faster rate of absorption than NA tablets

Delayed absorption with delayed-release tablets; valproate «s rapidly converted to VPA in the intestine, then s rapidly and almost completely absorbed from theGltiact Extended release bioavailability is approxirrately 15% less than delayed release Yes; food slows the rate of absorption bui not the extent for O/P

1-4 hours (VPA) 3-5 hours (DVP s«>gle dose) 7-14 hours (DVP extended idease multiple dosing)

Btoavadability not affected by food

1-4 hours

Distribution

Volume of distribution

Crosses the placenta

Crosses into breast

Protein binding Renal clearance

Yes; pregnancy risk category: D fiiskofcar<toc defects: 0.1-05% Yes: 35-50% Of mother's serum concentiation; breast-feeding not recommended

Yes; 10-40 ml7min with 90-98% of dose excreted in urine; 80% of lithium that is filtered by the renal glomeruli is reabsorbed

Yes pregnancy risk category. D

Yes ratio oí concentration m breast rrdk to pasma is 0.4 for drug and 0.5 for epoxide met aboi te considered compilable with beast-feed ng 75-90%

Yes 1-3% excreted uxhanged in urine

10-monohydroxy 11 L/1.73 nr (total valproate*

caiba/epine 921/1.73 rrv' (free valproate) (metabolite): 49 LAg

Yes; pregnancy risk Yes: pregnancy risk category. D

categoiy C R<sk of neural tube defects: 1-5%

Yes both drug and active metabolite breastfeeding no? recommended

40% of active metabolite

Yes; 9S% exacted Yes: 30-50% excreted as in the urine less ghicuronide conjugate; less than 1% excreted than 3% excreted unchanged unchanged

Yes: considered compatible with breast-feeding

80-90% (dose deperxfcnt)

Yes; pregnancy risk category C

Yes; breastfeeding not recommended

Yes; 94% excreted as glucurontde conjugate

Cytochrome P*50 (CTPISOi Isoenzyme

50 substrate CYPJiOifihliiK* CYP450 indutFJ

No No No

KSand3A3/4 Unknown

Hi 2CI9

1JJ. nnd 3-VVJ

3Cli

Cytochrome P*50 (CTPISOi Isoenzyme

50 substrate CYPJiOifihliiK* CYP450 indutFJ

No No No

KSand3A3/4 Unknown

Hi 2CI9

1JJ. nnd 3-VVJ

3Cli

Unknown Unknown Unknown

Thnrapwitlc ScruiTi.'Pliima iantentriEnani

Otjia in blood If^iel l-ljraEdl.

10-12 Ivxns

(inmaVLfc 1or

(mmoi/L^ far e Wdly Of medically ill flji-1.2 mfcq/L (nmrf/L)-lor adult ■rtHrtlenanoe

4-1 ? miigtinL 117-51 Klo wtahlish«l 50-12S mtgvlmL Citl7-i)6t

|jrnol/li foi adull, ¿cub? mama and maintenance 4-8 mc^mL: Ibi elderly or medically ill

Ihcraptiulk range; 1J-30 mcg/mL for 10 F^circKy carfi ¿repine based on fpilppiyUflatt

I irmi'l i adult, aculc <mnia arxl imalnienanne JQ-75 mc^irf. elderly of medically ill

Ho established thdaptutk: rang?:4-iO fflOQM.ftA-SO urrtolASlHwd cm epilepsy trials

DW divalproex; NA. not applicable; VP^ valproic acid. From fteft, 28, 30,33- 35.

DVP Sodium and Valproic Acid

DVP sodium is comprised of sodium valproate and VPA. The delayed-release and extended-release formulations are converted in the small intestine into VPA, which is the systemically absorbed form. It was developed as an anticonvulsant, but also has efficacy for mood stabilization and migraine headaches. It is FDA approved for the treatment of the manic phase of bipolar disorder. It is generally equal in efficacy to lithium and some other drugs for bipolar mania. It has particular utility in bipolar disorder patients with rapid cycling, mixed mood features, and substance abuse comor-bidity. Although not FDA approved for relapse prevention, studies support this use, and it is widely prescribed for maintenance therapy. DVP can be used as monotherapy or in combination with lithium or an antipsychotic drug.

Mechanism of Action. The mechanism of action of DVP is not well understood. It is known to affect ion transport and enhances the activity of gamma-aminobutyric acid (GABA). Like lithium, it also has possible neuroprotective effects through enhancement of BDNF.31

Table 39-6 Guidelines for Baseline and Routine Laboratory Tests and Monitoring for Agents Used in the Treatment of Bipolar Disorder

■•kbHin*:

Ptignlüd

Eh^nwMiiion

indCmiit

HHTU

1-SlHJK

Llm Fun

ctlon

ftvnaJ Fnlhai

1hï|-ia4d fwK'lkHi

Scrum

Ch+nwci^

MitaJwlk T#«s

T*«S

T«t+-

TÉ^ÎS

4-12

4-12

«-1Î

6-11

•S-1Ï

J-+

n-i Mer*?M

Ü Sirnlhi

tlMl-l*

rm

Mcnlhï

tflHlm

(«Felm*

■"■J -, j:-:-J .jm^hifi.:',-

«: x

CjftHTTlUSffriP

X

K

X

K

X

X

X X

1 aiKinjur1,

ft

X X

Liyjym'

K

x

x

IC K

X

K

I

X X

OKsirtiaH-frt-pi^

K

X

X

vjijiojip"

x

X

%

K X

X

X X

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Dosing and Monitoring. DVP is usually initiated at 500 to 1,000 mg/day, but studies indicate a therapeutic serum VPA concentration can be reached more quickly through a loading dose approach of 20 to 30 mg/kg/day. Using this approach, patients may respond with a significant reduction in symptoms within the first few days of treatment. The dosage is then titrated according to response, tolerability, and serum concentration. The most often referenced desired VPA serum concentration is 50 to 125 mcg/

mL (347-866 ^moles/L), but it is not unusual for patients to require more than 100 mcg/mL (693 p,moles/L) for optimal efficacy. Some patients require high milligram dosages in order to reach a desired serum concentration. The suggested serum concentration range is based on morning sampling, which is a trough value for patients taking divided daily dosing. Serum concentration monitoring is recommended at least every 2 weeks until stabilized, then less frequently, sometimes as infrequently as twice yearly. The extended-release formulation can be taken once daily (see Table 39-4). If administered at night, a morning blood sampling is not an actual trough. The drug could be given in the morning so that blood sampling the following day would be a trough value and more easily interpreted. The systemic bioavailability of extended-release DVP is about 15% less than that of the delayed-release formulation. Patients who have difficulty swallowing large tablets can use the sprinkle formulation. The immediate-release formulation, either capsules or syrup, is generally given three or

four times per day.

Adverse Effects. The most common adverse effects of DVP are GI (loss of appetite, nausea, dyspepsia, diarrhea), tremor, and drowsiness. GI distress can be reduced by coadministration with food. The delayed-release and extended-release formulations are less likely to cause gastric distress than the immediate-release VPA. This is an advantage for DVP, along with fewer daily doses, which can improve patient adherence to treatment. Dosage reduction can reduce all of the common DVP side effects. As with lithium, a low-dose P-blocker may alleviate the tremor. Weight gain is also common, occurring in up to 50% of patients on maintenance therapy. 0

Other adverse effects that are less common include alopecia or a change in hair color or texture. Hair loss can be minimized by supplementation with a vitamin containing selenium and zinc. Polycystic ovarian syndrome associated with increased androgen production has been reported. Thrombocytopenia is not uncommon, and the platelet count should be monitored periodically. It is a dose-related adverse effect and usually asymptomatic, but the drug is usually stopped if the platelet count decreases to less than 100 x 103/mm3 (100 x 109/L). More rare are hepatic toxicity and pancreatitis, which are not always dose related. Severe GI symptoms of hepatic or pancreatic toxicity include vomiting, pain, and loss of appetite. When these occur the patient should be evaluated for possible hepatitis or pancreatitis. DVP has a wide therapeutic index. Acute toxicity for high dosages or overdosage is not life-threatening.30

Drug Interactions. Drug interactions involving DVP are common. It is a weak inhibitor of some of the drug metabolizing liver enzymes and can affect the metabolism of other drugs. These include other anticonvulsants and tricyclic antidepressants. The interaction between DVP and lamotrigine is particularly important. The risk of a dangerous rash due to lamotrigine is increased when given concurrently with DVP. When lamotrigine is added to DVP, the initial lamotrigine dosage should be half the typical starting dosage, and lamotrigine should be titrated more slowly than usual. When DVP is added to lamotrigine, the lamotrigine dosage should be reduced by 50%. Conversely, the metabolism of DVP can be increased by enzyme-inducing drugs such as carbamazepine and phenytoin, while DVP may simultaneously slow metabolism of the other agents.29

Carbamazepine

Although long utilized as a mood stabilizing drug, only the extended-release formulation of carbamazepine has received FDA approval for treatment of bipolar disorder. Like DVP, it also has efficacy for mood stabilization, but is considered possibly less desirable as a first-line agent because of safety and drug interactions. It is sometimes reserved for patients who fail to respond to lithium or for patients with rapid cycling or mixed bipolar disorder. Carbamazepine can be used as monotherapy or in combin-

32 33

ation with lithium or an antipsychotic drug. '

Mechanism of Action. The mechanism of action of carbamazepine is not well understood. It blocks ion channels and inhibits sustained repetitive neuronal excitation, but

whether this explains its efficacy as a mood stabilizing drug is not known.

Dosing and Monitoring. Carbamazepine is usually initiated at 400 to 600 mg/day. The sustained-release formulation can be given in two divided doses. In addition to a formulation that is completely sustained-release, an additional extended-release formulation contains a matrix of 25% immediate-release, 40% extended-release, and 35%

enteric-release beads. The suggested therapeutic serum concentration is 4 to 12 mcg/ mL (17-51 ^mol/L). As with DVP, some patients require high milligram dosages to achieve a desired serum concentration and therapeutic effect. The dosage can be increased by 200 to 400 mg/day as often as every 2 to 4 days to achieve the desired effect. Serum concentration monitoring is suggested at least every 2 weeks until sta-

bilized, then less frequently.

Adverse Effects. The most common adverse effects are drowsiness, dizziness, ataxia, lethargy, and confusion. At mildly toxic serum concentrations, it also causes diplopia and dysarthria. These effects can be minimized through dosage adjustments, use of sustained-release formulations, and giving more of the drug late in the day. GI upset is also common. Carbamazepine has an antidiuretic effect similar to the syndrome of inappropriate antidiuretic hormone secretion and can cause hyponatremia. Mild elevations in liver enzymes can occur, but hepatitis is less common. Mild, dose-related leukopenia is not unusual and not usually an indication for stopping the drug. More serious blood count abnormalities such as aplastic anemia and agranulocytosis are

rare, but life-threatening. Suggested baseline and routine laboratory monitoring is reviewed in Table 39-6.

Drug Interactions. Carbamazepine induces the hepatic metabolism of many drugs, including other anticonvulsants, antipsychotics, some antidepressants, oral contraceptives, and antiretroviral agents. Carbamazepine is also an autoinducer, i.e., it induces its own metabolism. The dosage may require an increase after 1 month or so of therapy because of this effect. Conversely, the metabolism of carbamazepine can be slowed by enzyme inhibiting drugs such as some antidepressants, macrolide antibiotics including erythromycin and clarithromycin, azole antifungal drugs including ketoconazole and itraconazole, and grapefruit juice. Carbamazepine should not be given concurrently

with clozapine because of the additive risk of agranulocytosis. Lamotrigine

Lamotrigine is effective for the maintenance treatment of bipolar disorder. It is more effective for depression relapse prevention than for mania relapse. Its primary limitation as an acute treatment is the time required for titration to an effective dosage. In addition to maintenance monotherapy, it is sometimes used in combination with lithium or DVP, although combination with DVP increases the risk of rash, and lamotrigine dosage adjustment is required.34

Mechanism of Action. The mechanism of action of lamotrigine appears to involve blockage of ion channels and effects on glutamate transmission, although the precise mechanism in bipolar disorder is not clear.34

Dosing and Monitoring. Lamotrigine is usually initiated at 25 mg daily for the first 1 to 2 weeks, then increasing in a dose-doubling fashion every 1 to 2 weeks to a target dosage of 200 to 400 mg/day. If lamotrigine is added to DVP, the starting dosage is 25 mg every other day with a slower titration to reduce the risk of rash. If DVP is added to lamotrigine, the lamotrigine dosage should be reduced by 50% for the same reason. If lamotrigine therapy is interrupted for more than a few days, it should be restarted at the initial dosage. Serum concentration monitoring is not routinely recommended for patients with bipolar disorder.34

Adverse Effects. The lamotrigine adverse effect of greatest significance is a maculo-papular rash, occurring in up to 10% of patients.34 Although usually benign and temporary, some rashes can progress to life-threatening Stevens-Johnson syndrome. The risk of rash is greater with a rapid dosage titration and when given concurrently with DVP or other metabolic enzyme inhibitors. The risk is minimal when the dosage titration schedule is slow. Other side effects include dizziness, drowsiness, headache, blurred vision, and nausea. In contrast to other mood stabilizing drugs such as lithium and DVP, lamotrigine does not significantly influence body weight.

Drug Interactions. Drug interactions involving lamotrigine are usually due to induction or inhibition of its metabolism by other drugs. It does not affect drug metabolizing hepatic enzymes on its own, but other drugs that affect these pathways can have a significant effect on lamotrigine's clearance. In particular, DVP slows the rate of elimination of lamotrigine by about half, necessitating dosage reduction. Conversely, car-

bamazepine increases the rate of lamotrigine metabolism. Upward adjustment in the

lamotrigine dosage may be needed as a result. Oxcarbazepine

Oxcarbazepine is an analogue of carbamazepine, developed as an anticonvulsant. An advantage over carbamazepine is that routine monitoring of hematology profiles and serum concentrations are not indicated as the drug is less likely to cause hematologic

abnormalities. Additionally, drug interactions are less significant, although it is at least a mild inducer of certain metabolic pathways, and vigilance for drug interactions is needed, especially with oral contraceptives. Oxcarbazepine appears in the most recent treatment algorithms for bipolar disorder,36 but clinical trial data are limited. A systematic review concluded that there are insufficient data from well-designed clin-

ical trials to provide guidance on its use.

Adverse Effects. Adverse effects due to oxcarbazepine include drowsiness, dizziness,

GI upset, and hyponatremia, the latter two of which may be more likely than with car-

bamazepine.

Others

High potency benzodiazepine agents such as clonazepam and lorazepam have been used as adjunctive therapy, especially during acute mania episodes, to reduce anxiety and improve sleep. Topiramate is commonly used for its putative mood stabilizing effects, but unpublished, well-designed, randomized, controlled trials sponsored by the manufacturer showed no difference between topiramate and placebo for treatment of bipolar disorder. Uncontrolled, open-label data suggest possible use as an adjunct-

ive agent. Gabapentin has shown no efficacy over placebo and is not recommended for patients with bipolar disorder. One of the few randomized, placebo-controlled trials of gabapentin in bipolar disorder actually showed a statistical inferiority compared to placebo.40 As complementary or alternative medicines gain wider usage, omega-3 fatty acids have been used in mood disorders. Insufficient well-designed studies exist to support a recommendation of routine use or to establish a place in therapy relative to usual therapies.

Antipsychotic Drugs

Conventional antipsychotic drugs such as chlorpromazine and haloperidol have long been used in the treatment of acute mania. Atypical antipsychotic drugs including aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone have been approved for the treatment of bipolar mania or mixed mood episodes as monotherapy or in com-

bination with mood stabilizing drugs. Aripiprazole, olanzapine, and quetiapine are also approved for maintenance therapy for prevention of manic relapse. The combination of olanzapine and fluoxetine is approved for treatment of acute bipolar depression. Quetiapine is approved as monotherapy for acute bipolar depression and as adjunctive therapy with lithium or DVP for prevention of bipolar depression relapse. Approval of antipsychotic drugs in bipolar disorder patients applies without regard to the presence of psychotic symptoms. In comparative studies, atypical antipsychotic drugs are equivalent in efficacy to lithium and DVP for treatment of acute mania. Treatment guidelines include antipsychotic drugs as first-line therapy.36 Of interest is evidence that the combination of mood stabilizing drugs and antipsychotic drugs is more likely

to achieve remission of acute manic episodes than monotherapy with either. The quetiapine data in relapse prevention of both manic and bipolar depression episodes likewise favored combination therapy over mood stabilizing drug monotherapy.41

The mechanisms of action, usual dosages, pharmacoki-netics, adverse effects, and drug interactions involving antipsychotic drugs are discussed in detail in the chapter on schizophrenia. Dosages in bipolar disorder are similar to those used in schizophrenia. Higher dosages are often required to treat an acute episode than to prevent relapse. The recommended dosage of aripiprazole for bipolar disorder is 20 to 30 mg/

day, somewhat higher than the average dosage used in schizophrenia. The recom mended dosage for quetiapine in treatment of acute bipolar depression is 300 mg/day, less than the 600 mg/day recommended in acute mania.43

Atypical antipsychotic drugs are less likely than conventional antipsychotics to cause neurologic side effects, especially movement abnormalities. As a group, however, they are more likely to cause metabolic side effects, such as weight gain, glucose dysregulation, and dyslipidemia44 Among the atypical antipsychotic drugs approved for treatment of bipolar disorder, olanzapine is more likely to cause metabolic side effects. Quetiapine and risperidone cause less metabolic effects than olan-zapine. Aripiprazole and ziprasidone are least associated with effects on weight, glucose, and lipids. Metabolic adverse effects data regarding paliperidone in acute and limited long-term studies show mild weight gain and little effect on glucose and lipids.45 More experience is needed to fully understand paliperidone's profile. Pal-iperidone is not FDA approved for bipolar disorder at present. The chapter on schizophrenia discusses adverse effects of antipsychotic drugs in more detail.

Antidepressants

Treatment of depressive episodes in bipolar disorder patients presents a particular challenge because of the risk of a drug-induced mood switch to mania, although there is not complete agreement about such risk. The FDA requires the product label of all antidepressant drugs to contain language about the potential risk of inducing a mood switch to mania. Randomized, controlled data show no advantage for adjunctive antidepressant use compared to mood stabilizer therapy alone.46 Treatment guidelines suggest lithium or lamotrigine as first-line therapy. ,47 However, the guidelines do not reflect the more recent data on olanzapine and quetiapine, discussed above. When usual treatment fails, efficacy data support use of antidepressants.21

Guidelines agree that when antidepressants must be used, they should be combined with a mood stabilizing drug to reduce the risk of mood switch to hypomania or mania.36,47 The question of which antidepressant drugs are less likely to cause a mood switch is not resolved, but tricyclic antidepressants are thought to carry a greater risk of treatment-emergent mania. A randomized comparison of venlafaxine, sertraline, and bupropion as adjunctive therapy to a mood stabilizer showed venlafaxine with the highest risk of a mood switch to mania or hypomania and bupropion with the least.48

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Anxiety and Depression 101

Anxiety and Depression 101

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