1-Definition:

Bipolar disorder "manic depressive disorder or manic depression", It's a serious mental illness, can lead to risky behavior, damaged relationships and careers, and even suicidal tendencies, if it's not treated, Bipolar disorder is characterized by extreme changes in mood (poles) from mania to depression, Bet een these mood s ings, a person ith bipolar disorder may experience normal moods! ""anic" describes an increasingly "restless, energetic, talkative, reckless, po erful, euphoric period", #hen, at some point, this high$flying mood can spiral into something darker "irritation, confusion, anger, feeling trapped"! "%epression" describes the opposite mood "sadness, crying, sense of orthlessness, loss of energy, loss of pleasure, sleep problems"! But because the pattern of highs and lo s varies for each person, bipolar disorder is a complex disease to diagnose! &or some people, mania or depression can last for eeks or months, even for years! &or other people, bipolar disorder takes the form of fre'uent and dramatic mood shifts (WebMD,2008)!

2-Risk factors:
lifestyle habits increase the risk of bipolar disorder, that lack of sleep increases the risk of having an episode of mania, In addition, antidepressant medications, particularly hen taken as the only medication, may also trigger a s itch into a manic state! (xcessive use of alcohol or drugs can also trigger bipolar symptoms! )esearch has sho n that about *+, of bipolar sufferers have a substance abuse or alcohol problem! -ufferers often use alcohol or drugs to self$medicate during their high and lo moods! .lso environmental stress that include seasonal changes, holidays, and ma/or life changes such as starting a ne /ob, losing a /ob, going to college, family disagreements, marriage, or a death in the family, increase the risk of bipolar disorder
(WebMD,2008)!

3-Epidemiology:
.pproximately *, of the adult population has either bipolar I or II disorder, ith the full spectrum of recurrent mood disorders (American Psychiatric Association ,2000)!

#he lifetime prevalence of bipolar I disorder (one or more manic or mixed episodes) is +!1, to 0!2,3 that for bipolar II disorder (recurrent ma/or depressive episodes ith hypomanic episodes) is approximately +!*,, Bipolar I disorder occurs e'ually in men and omen, hereas bipolar II disorder is more common in omen (American Psychiatric
Association,2000 ; American Psychiatric Association,2002)!

4-Etiology:
#he exact etiology of bipolar disorder is unkno n! Bipolar disorder is thought to be a complex genetic disease that is environmentally influenced and caused by a ide range of neurobiologic abnormalities! -tressful life events, alcohol or substance use, and changes in the sleep$ ake cycle can elicit the expression of genetic or biologic vulnerabilities that cause dysregulation of neurotransmitters, neuroendocrine path ays, and second messenger systems (Goldberg et al,1 4.1-Neurochemical theories: %ysregulation bet een neurotransmitters, neuropeptides, hormones, and secondary messenger systems can produce a cyclic rhythm disturbance in the central nervous system (!orrey, "nable, 2002)! #he "permissive serotonin hypothesis" proposes that serotonin (*$4#) plays a critical role in modulating brain activity (e!g!, stabilization of the catecholamine system and inhibition of dopamine (%.) release), and is lo in both mania and depression, #he type of affective state that is expressed ith the permissive hypothesis is determined secondarily by the level of norepinephrine (5() (e!g!, increased amounts of 5( lead to mania, decreased amounts lead to depression), *$4# deficiency and changes in the light6dark cycle may result in reduced melatonin secretion from the pineal gland that disrupts the sleep ake cycle, alters circadian rhythms, and causes seasonal affective changes (Goodnic# et al, 1
8; Mahmood et al, 2001)! )!

#he catecholamine hypothesis of mood disorders suggests that increased %. and 5( activity contribute to hyperactivity and psychosis associated ith the severe stages of mania, and reduced activity causes depression (Goodnic# et al, 1 inhibits 5( and %. activity (Goodnic# et al, 1
8; Goldberg et al, 1 )!

. 7$aminobutyric acid (8.B.) deficiency theory has been proposed for mania as it
8; Goldberg et al, 1 )!

8lutamate and aspartate, excitatory amino acid neurotransmitters, may be overactive and involved in causing manic episodes (Man$i et al, 2000)! 9

:holinergic under activity has been proposed to cause mania and over activity of acetylcholine to cause depression (Goodnic# et al, 1
8; Man$i et al, 2000)!

4.2- ummari!es the etiologic theories of "ipolar disorder:

4.2.1-#enetic factors: ;+6<+, of patients ith bipolar disorder have a biologic relative ith a mood disorder (e!g!, bipolar disorder, ma/or depression, cyclothymia, or dysthymia)! &irst$degree relatives of bipolar patients have a 0*6=*, lifetime risk of developing any mood disorder and a *60+, lifetime risk for developing bipolar disorder! #he concordance rate of mood disorders is 2+6;+, for monozygotic t ins and 0169+, for dizygotic t ins! >inkage studies suggest that certain loci on genes and the ? chromosome may contribute to genetic susceptibility of bipolar disorder! 4.2.2-Nongenetic factors: $erinatal insult. %ead trauma. En&ironmental factors: %eschronization of circadian or seasonal rhythms cause diurnal variations in mood and sleep patterns and can result in seasonal recurrences of mood episodes! :hanges in the sleep$ ake cycle or light$dark cycle can precipitate episodes of mania or depression! Bright light therapy can be used for the treatment of inter depression and can precipitate hypomania, mania, or mixed episodes! $sychosocial or physical stressors: -tressful life events often precede mood episodes and can increase recurrence rates and prolong time to recovery from mood episodes! Nutritional factors: %eficiency of essential amino acid precursors in the diet can cause a dysregulation of neurotransmitter activity (e%g!, >$tryptophan deficiency causes a decrease in *$4# and melatonin synthesis and activity)! =

%eficiency in essential fatty acids (e%g!, omega$= fatty acids) can cause a dysregulation of neurotransmitter activity! Neurotransmitter'neuroendocrine'hormonal theories: %ysregulation bet een excitatory and inhibitory neurotransmitter systems3 excitatory@ 5(, %., glutamate, and aspartate3 inhibitory@ *$4# and 8.B.! (onoamine hypothesis: .n excess of catecholamines (primarily 5( and %.) cause mania! .gents that decrease catecholamines are used for the treatment of mania (e!g!, %. antagonists and A9$adrenergic agonists)! %eficit of neurotransmitters (primarily 5(, %., andBor *$4#) cause depression! .gents that increase neurotransmitter activity are used for the treatment of depression (e!g!, *$4# and 5(B%. reuptake inhibitors and ".CIs)! Dysregulation of amino acid neurotransmitters: %eficiency of 8.B. or excessive glutamate activity causes dysregulation of neurotransmitters (e!g!, increased %. and 5( activity)! .gents that increase 8.B. activity or decrease glutamate activity are used for the treatment of mania and for mood stabilization (e!g!, benzodiazepines, lamotrigine, lithium, or valproic acid)! )holinergic hypothesis: %eficiency of acetylcholine causes an imbalance in cholinergic$adrenergic activity and can increase the risk of manic episodes! .gents that increase acetylcholine activity can decrease manic symptoms (e!g!, use of cholinesterase inhibitors or augmentation of muscarinic cholinergic activity)! Increased central acetylcholine levels can increase the risk of depressive episodes! .gents that decrease acetylcholine activity can alleviate depressive symptoms (i!e!, anticholinergic agents)! econdary messenger system dysregulation: .bnormal 8 protein functioning dysregulates adenylate cyclase activity, phosphoinositide responses, sodiumBpotassiumBcalcium channel exchange, and activity of phospholipases! .bnormal cyclic adenosine monophosphate and phosphoinositide secondary messenger system activity! 1

.bnormal protein kinase : activity and signaling path ays! %ypothalamic-pituitary-thyroid a*is dysregulation: 4yperthyroidism can precipitate manic$like symptoms! 4ypothyroidism can precipitate a depression and be a risk factor for rapid cycling3 thyroid supplementation can be used for refractory rapid cycling and augmentation of antidepressants in unipolar depression! Dositive antithyroid antibody titers reported in patients ith bipolar disorder! 4ormonal changes during the female life cycle can cause dysregulation of neurotransmitters (e!g!, premenstrual, postpartum, and perimenopause)! (em"rane and cation theories: .bnormal neuronal calcium and sodium activity and homeostasis cause neurotransmitter dysregulation! 4ypocalcemia has been associated ith causing anxiety, mood irritability, mania, psychosis, and delirium! 4ypercalcemia has been associated ith causing depression, stupor, and coma! (xtra cellular and intracellular calcium concentrations may affect the synthesis and release of 5(, %., and *$4#, as ell as the excitability of neuronal firing! ensiti!ation and kindling theories: )ecurrences of mood episodes causes behavioral sensitivity and electro physiologic kindling (similar to the amygdalakindling models for seizures in animals) and can result in rapid or continuous mood cycling (Di&iro et al, 2008)!

+-)linical presentation:
#he essential feature of bipolar spectrum disorders are a history of mania or hypomania that is not caused by any other medical condition, substance, or psychiatric disorder! Bipolar disorder is divided into four subtypes based on the identification of specific mood episodes@ bipolar I, bipolar II, cyclothymic disorder, and bipolar disorder not other ise specified! (ood Disorders Defined "y Episodes: Disorder u"type:
"a/or depressive disorder, single episode "a/or depressive disorder, )ecurrent

Episode,s"a/or depressive episode # o or more ma/or depressive episodes

Bipolar disorder, type I Bipolar disorder, type II %ysthymic disorder :yclothymic disorder Bipolar disorder not other ise -pecified

"anic episode E ma/or depressive or mixed episode "a/or depressive episode F hypomanic episode :hronic subsyndromal depressive episodes :hronic fluctuations bet een subsyndromal depressive and hypomanic episodes (9 years for adults and 0 year for children and adolescents) "ood states do not meet criteria for any specific bipolar disorder

#he length and severity of a mood episode and the interval bet een episodes varies from patient to patient! "anic episodes are usually briefer and end more abruptly than ma/or depressive episodes! #he average length of untreated manic episodes ranges from 1 to 0= months! (pisodes can occur regularly (at the same time or season of the year) and often cluster at 09$month intervals! Gomen have more depressive episodes than manic episodes, hereas men have a more even distribution of episodes! &or bipolar I disorder, <+, of individuals ho experience a manic episode later have multiple recurrent ma/or depressive, manic, hypomanic, or mixed episodes alternating ith a normal mood state! .pproximately *60*, of patients ith bipolar II disorder ill develop a manic episode over a *$year period! If a manic or mixed episode develops in a patient ith bipolar II disorder, the diagnosis is changed to bipolar I disorder! Datients ith cyclothymic disorder have a 0*6*+, risk of later developing a bipolar I or II disorder (American Psychiatric Association,2002)! +.1- ymptoms of the depressi&e phase of "ipolar disorder may consist of the follo.ing: %epressed mood and lo self$esteem! (xcessive crying spells! >o energy levels and an apathetic vie of life! -adness, loneliness, helplessness, feelings of guilt! -lo speech, fatigue, and poor coordination and concentration! Insomnia or oversleeping! #houghts of suicide or dying! :hanges in appetite (overeatingBnot eating)! %rug use@ self$medication through illicit drugs! 2

Hnexplainable aching! >ack of interest or pleasure in usual activities! +.2- ymptoms of "ipolar mania or hypomania may contain: (uphoria or irritability! (xcessive talking, racing thoughts! Inflated self$esteem! Hnusual energy3 less need for sleep! .lcohol and illicit drug use $ cocaine and methamphetamines! Impulsiveness, a reckless pursuit of gratification, shopping sprees, impetuous travel, more and sometimes promiscuous sex, high$risk business investments, fast driving! 4allucinations and or delusions (in extreme cases of bipolar disorder ith psychotic features) (WebMD,2008)! But bipolar disorder can be sneaky, -ymptoms can defy the expected manic$depressive se'uence, Infre'uent episodes of mild mania can go undetected, %epression can overshado other aspects of the illness, .nd substance abuse can cloud the picture! #aken together, these factors make bipolar disorder surprisingly difficult to diagnose! +.3-/ fe. facts a"out "ipolar disorder: .s many as 9+, of people complaining of depression to their doctor actually have bipolar disorder! .bout half of people ith bipolar disorder have seen three professionals before being diagnosed correctly! It takes an average of 0+ years for people to enter treatment for bipolar disorder after symptoms begun! Dartly, this is due to delays in diagnosis (WebMD,2008)!

0-Diagnosis and difficulties:

#he .merican Dsychiatric .ssociation has established a long list of specific criteria for recognizing the disorder! (valuation involves investigating the patient's history and any family history of mood s ings or suicide! Cther disorders must be ruled out particularly such childhood problems as school phobia and attention deficit disorder, aging problems of dementia, schizophrenia, schizoaffective disorder, and other psychotic states induced solely by alcohol or drugs! %rug or alcohol abuse is common in persons I

ith bipolar disorder and can mask the symptoms, thus complicating diagnosis and treatment! )ecognizing and treating any drug abuse is a priority, since it is a strong predictor of suicide, especially in men! Before treatment begins, the patient receives a careful physical exam, and blood and urine are tested to detect conditions that could put medical constraints on the choice of treatment! . thyroid analysis is particularly important both because hyperthyroidism can look like mania and because lithium "the principal drug treatment for bipolar disorder" is kno n to lo er thyroid function andBor impair kidney function! %uring treatment, fre'uent blood tests are necessary to see that ade'uate drug levels have been reached and to detect adverse reactions at an early stage
(WebMD,2008)!

-everal medical, medication$induced, or substance$related causes of mania and depression have been identified, . complete medical, psychiatric, and medication history, physical examination, and laboratory testing are necessary to rule out any organic causes of mania or depression (American Psychiatric Association,2002)! 0.1- econdary causes of mania: (edical conditions that induce mania:

1- )N disorders: Brain tumor, -trokes, 4ead in/uries, -ubdural hematoma, "ultiple -clerosis, -ystemic >upus (rythematosus, #emporal lobe seizures, 4untingtonJs disease! 2- 1nfections: (ncephalitis, 5eurosyphilis, -epsis, 4uman immunodeficiency virus! 3- Electrolyte or meta"olic a"normalities: :alcium or -odium fluctuations, 4yper or 4ypoglycemia! 4- Endocrine or hormonal dysregulation: .ddisonJs disease, :ushingJs disease, 4yper or 4ypothyroidism, "enstrual$related or Dregnancy$related or Derimenopausal mood disorders! (edications or drugs that induce mania: .lcohol intoxication. %rug ithdra al states (alcohol, A9$adrenergic agonists, antidepressants, barbiturates, benzodiazepines, opiates)! .ntidepressants (".CIs, #:.s, *$4# andBor 5( andBor %. reuptake inhibitors, *$4# antagonists)! %.$augmenting agents (:5- stimulants@ amphetamines, cocaine, sympathomimetics, %. agonists, releasers, and reuptake inhibitors)! ;

4allucinogens (>-%, D:D)! "ari/uana intoxication precipitates psychosis, paranoid thoughts, anxiety, and restlessness! 5($augmenting agents (A9$adrenergic antagonists, K$agonists, 5( reuptake inhibitors)! -teroids (anabolic, adrenocorticotropic hormone, corticosteroids)! #hyroid preparations! ?anthines (caffeine, theophylline)! Cver$the$counter eight loss agents and decongestants (ephedra, pseudo ephedrine)! 4erbal products (-t! LohnJs ort)! omatic therapies that induce mania: Bright light therapy! -leep deprivation! 0.2- econdary causes of depression: #eneral medical conditions:

1-Endocrine diseases: 4ypothyroidism2 .ddison or :ushing disease. 2-Deficiency states: Dernicious anemia2 Gernicke encephalopathy , -evere anemia. 3-1nfections: .I%-, (ncephalitis, 4uman immunodeficiency virus, "ononucleosis! -exually transmitted diseases , #uberculosis! 4-)ollagen disorder: -ystemic lupus erythematosus! +-(eta"olic disorders: (lectrolyte imbalance,(4ypokalemia, 4yponatremia), 4epatic encephalopathy! 0-)ardio&ascular disease: :oronary artery disease, :ongestive heart failure, "yocardial infarction! 3-Neurologic disorders: .lzheimerJs disease, (pilepsy, 4untingtonJs disease, "ultiple sclerosis, Dain, DarkinsonJs disease, Dost stroke! 4-(alignant disease. (edications or drugs that induce depression: u"stance use disorders ,including into*ication and .ithdra.al-: .lcoholism. "ari/uana abuse and dependence. 5icotine dependence! Cpiate abuse and dependence (e!g!, heroin)! <

Dsychostimulant abuse and dependence (e!g!, cocaine)! Drug therapy: .ntihypertensives@ :lonidine, %iuretics, 8uanethidine sulfate, 4ydralazine hydrochloride, "ethyldopa, Dropranolol, )eserpine! %ormonal therapy: Cral contraceptives! -teroidsBadrenocorticotropic hormone! /cne therapy: Isotretinoin! 5ther: Interferon$K0a! .n accurate diagnosis is important because some psychiatric and neurologic disorders present ith manic$like or depressive$like symptoms, &or example, attention$ deficitBhyperactivity disorder and a manic episode have similar characteristics3 thus individuals ith bipolar disorder can be misdiagnosed and prescribed central nervous system stimulants! .nother disease state that has a similar presentation to bipolar disorder is schizoaffective disorder! #his disease is a mix bet een schizophrenia and bipolar disorder! Datients ith schizoaffective disorder have mood episodes, but the distinguishing factor from bipolar disorder is that these patients experience psychosis even bet een mood episodes during periods of euthymia (Di&iro et al, 2008)! 0.3-Diagnostic criteria of mood episodes: 0! "ental status examination! 9! Dsychiatric, medical, and medication history! =! Dhysical and neurologic examination! 1! Basic laboratory tests@ complete blood count, blood chemistry screen, thyroid function, urinalysis, urine drug screen! *! Dsychological testing! 2! Brain imaging@ magnetic resonance imaging and functional scan3 alternative@ computed tomography scan, positron emission tomography scan! I! >umbar puncture! ;! (lectroencephalogram!

0+

3-)ourse of illness:
#he average age of onset of a first manic episode is 90 years! "ore than ;+, of bipolar patients have more than four episodes during their lifetime! Hsually there is normal functioning bet een episodes! )apid cyclers (0+, to 9+, of bipolar patients) have four or more episodes per year (ma/or depressive, manic, mixed, or hypomanic)! )apid$ cycling and mixed states are associated ith a poorer prognosis and nonresponse to antimanic agents! )isk factors for rapid cycling include biologic rhythm dysregulation, antidepressant or stimulant use, hypothyroidism, and premenstrual and postpartum states! -uicide attempts occur in up to *+, of patients ith bipolar disorder, and approximately 0+, to 0<, of individuals ith bipolar I disorder commit suicide! Bipolar II patients may be more likely than bipolar I patients to attempt suicide! Bipolar patients ith substance abuse disorders are more likely to have an earlier onset of illness, mixed states, higher relapse rates, poorer response to treatment, higher suicide risk, and more hospitalizations! (pisodes may become longer in duration and more fre'uent ith aging (American Psychiatric Association,2002)!

4-6reatment:
4.1-#eneral principles for the management of "ipolar disorder: #oals of treatment: M (liminate mood episode ith complete remission of symptoms (i!e!, acute treatment)! M Drevent recurrences or relapses of mood episodes (i!e!, continuation phase treatment)! M )eturn to complete psychosocial functioning! M "aximize adherence ith therapy! M "inimize adverse effects! M Hse medications ith the best tolerability and fe est drug interactions! M #reat comorbid substance use and abuse! M (liminate alcohol, mari/uana, cocaine, amphetamines, and hallucinogens! M "inimize nicotine use and stop caffeine intake at least ; hours prior to bedtime! M .voidance of stressors or substances that precipitate an acute episode!

00

#reatment of bipolar disorder must be individualized because the clinical presentation, severity, and fre'uency of episodes vary idely among patients! #reatment approaches should include both nonpharmacologic and pharmacologic strategies (Goldberg et al,1 Datients and family members should be educated about bipolar disorder (e!g!, symptoms, causes, and course) and treatment options! >ong$term adherence to treatment is the most important factor in achieving stabilization of the disorder! #he treatment of bipolar disorder can vary depending on hat type of episode a patient is experiencing! Cnce diagnosed ith bipolar disorder patients should remain on a mood stabilizer (e!g! lithium, valproate) for life! %uring acute episodes medications can be added and then tapered once a patient is stabilized and euthymic! &or example, hen treating a patient for mania ith psychotic features, the patient should be on a mood stabilizer and antipsychotic! If the antipsychotic is the patientJs maintenance therapy, the dose should be increased or perhaps changed altogether! If treating a patient for a severe depressive episode, add an antidepressant to the mood stabilizer and an antipsychotic if psychosis is also present (Di&iro et al, 2008)! 4.2-Nonpharmacologic therapy: #he basics of nonpharmacologic approaches are of ade'uate nutrition, sleep, exercise, and stress reduction! -leep deprivation, high stress, and deficiencies in dietary essential amino acids, fatty acids, vitamins, and minerals can exacerbate mood episodes and result in poorer outcomes (Goldberg et al,1
)! )!

.nother effective treatment is to combine medications ith ad/unctive psycho educational programs, supportive counseling, insight$oriented psychotherapy (individual or group), couples or family therapy, cognitive behavioral therapy, and communication enhancement training! 4.2.1-6ypes of psychotherapy used to treat "ipolar disorder include: 7eha&ioral therapy: #his focuses on behaviors that decrease stress! )ogniti&e therapy: #his type of approach involves learning to identify and modify the patterns of thinking that accompany mood shifts! 1nterpersonal therapy: #his involves relationships and aims to reduce strains that the illness may place upon them! ocial rhythm therapy: #his helps them develop and maintain daily routines! 09

-upport groups also help patients ith bipolar disorder, that receive encouragement, learn coping skills, and share concerns, they may feel less isolated as a result! &amily members and friends may also benefit from a support group! #hey can gain a better understanding of the illness, share their concerns, and learn ho to best support loved ones ith bipolar disorder (WebMD,2008)! 4.2.2-Electrocon&ulsi&e therapy ,E)6- is sometimes used for severely manic or depressed patients and for those ho don't respond to medication or for those omen ho, hile pregnant, experience symptoms! Because it acts 'uickly, it can also help patients ho are considered to be at high risk for committing suicide! (:# fell out of favor in the 0<2+s, but the procedure has been greatly refined since then! #he patient is first anesthetized and a drug to prevent muscle contraction is given! #hen an electric current is passed through the brain to produce a grand mal seizure of short duration " no more than a fe seconds"! %uring the course of (:# treatments usually t o to three eeks lithium and other mood stabilizers are discontinued to ensure an ade'uate response to the electrical stimulation! #he ne er types of non$pharmocological treatments of depression are@

8N ,8agal Ner&e timulation-. 6( ,6ranscranial (agnetic timulation-. >ight therapy has proved effective as an additional treatment hen bipolar disorder has a connection to the inter depression condition seasonal affective disorder! &or those people ho usually become depressed in inter, sitting for 9+$=+ minutes a day in front of a special light box ith a full$spectrum light can effectively treat their depression
(WebMD,2008)!

#he use of (:# for severe episodes of mania, depression, psychotic features (e!g!, hallucinations or delusions), mixed episodes, or rapid cycling is still considered the best acute treatment approach for those patients ho do not respond to first$line mood stabilizers such as lithium and valproate (Goldberg et al,1 4.2.3-Dietary intake: %isturbances in *$4# neurotransmission secondary to inade'uate dietary >$tryptophan or abnormalities in tryptophan hydroxylase, *$4# transporters, and *$4# receptors as implicated in the pathophysiology of manic depressive illness as early as 0<*;, If 0=
)!

available *$4# is lo , the synthesis and secretion of melatonin can be disrupted, thus causing circadian rhythm changes (Goodnic# et al, 1
8)!

. dietary deficiency in essential fatty acids (found in certain fish oils and flaxseed oil that contains A$linolenic acid) has been proposed as a potential cause of mood disorders, Cmega$= fatty acids have been sho n to suppress neuronal path ays and inhibit kindling processes by several mechanisms (e!g!, inhibition of phosphatidylinositol and 8$protein secondary messengers and blocking >$type calcium channels)! -eafood and fish are rich dietary sources of omega$= essential fatty acids, specifically docosahexaenoic acid and eicosapentaenoic acid (Par#er et al, 200')! 4.3-$harmacologic therapy: Dharmacotherapy is crucial for the acute and maintenance treatment of bipolar disorder and includes lithium, valproate, carbamazepine, lamotrigine, atypical antipsychotics, and ad/unctive agents such as antidepressants and benzodiazepines (Di&iro et al, 2008)! #he term mood stabilizer is often used to describe the class of medications used in the treatment of bipolar disorder, but this may not be accurate as some medications are more effective for acute mania, some for the depressive episode, and others for the maintenance phase! >ithium, valproate (or divalproex sodium), aripiprazole, olanzapine, 'uetiapine, risperidone, and ziprasidone are currently approved by the &ood and %rug .dministration (&%.) for the treatment of acute mania in bipolar disorder3 only lithium, olanzapine, and lamotrigine are approved for the maintenance treatment of bipolar disorder! Nuetiapine is the only antipsychotic that is &%. approved for bipolar depression! >ithium is the drug of choice for bipolar disorder ith euphoric mania, hereas valproate has better efficacy for mixed states, irritableBdysphoric mania, and rapid cycling compared to lithium (American Psychiatric Association,2002)! :ombination therapies (e!g!, lithium plus valproate or carbamazepine3 lithium or valproate plus an atypical antipsychotic) can provide better acute response and long$ term prevention of relapse and recurrence than monotherapy in some bipolar patients particularly those ith mixed states or rapid cycling! #here are fe controlled studies in children and adolescents ith bipolar disorder, thus little is kno n about the long$term efficacy and safety of specific agents or for combination therapies in this population
(American Psychiatric Association,2002; Goldberg et al,1 )!

4.3.1-#eneral information regarding efficacy and safety: >ithium as first used in 0<1< as a treatment for mania and as approved in 0<I9 in the Hnited -tates for the treatment of acute mania and for maintenance therapy! 01

>ithium as the first established mood stabilizer, and is still considered a first$line agent for acute mania and continuation treatment of bipolar I and II disorders (Goldberg et
al,1 )!

>ithium is the only bipolar medication approved for children and adults aged 09 years and older! >ong$term lithium treatment has been sho n to reduce suicide risk in several studies, Datients ith rapid cycling or mixed states may not respond as ell to lithium monotherapy compared to some anticonvulsants >ithium re'uires regular assessment of renal and thyroid functioning and lithium blood level monitoring to minimize adverse effects (American Psychiatric Association,2002)! %ivalproex sodium (kno n as sodium valproate) as marketed in 0<<* for the acute treatment of mania in adults and is no the most prescribed mood stabilizer in the Hnited -tates! %ivalproex sodium is &%. approved only for the treatment of acute manic or mixed episodes3 ho ever it is commonly used in clinical practice as maintenance monotherapy for bipolar disorder! .lthough carbamazepine is commonly used for both acute and maintenance therapy, it is not approved in the Hnited -tates for bipolar disorder! #here are some data to support the use of oxcarbazepine, a 0+$keto analogue of carbamazepine, in the treatment of bipolar disorder, ho ever it is not approved for the treatment of bipolar disorder in the Hnited -tates! Oalproate, carbamazepine, and oxcarbazepine each have a ide range of neurologic, gastrointestinal, electrolyte, and hematologic adverse effects that re'uires regular assessment and routine blood test (Di&iro et al, 2008)! >amotrigine, a ne er anticonvulsant, as approved in 9++= in the Hnited -tates for the maintenance treatment of bipolar I disorder ((alabrese et al, 2002; )*rley +(, 2002), >amotrigine add$on or monotherapy has been used for treatment refractory bipolar depression (American Psychiatric Association,2002; (alabrese et al, 2002), >amotrigine is associated ith causing hypersensitivity reactions and rare life$threatening skin rashes and re'uires slo dosage titration (American Psychiatric Association,2002)! .typical antipsychotics such as aripiprazole, olanzapine, 'uetiapine, risperidone, and ziprasidone are effective as monotherapy or ad/unctive therapy ith lithium and valproate in the treatment of acute mania (Perlis et al, 200'), -ome antipsychotics have the potential to cause adverse effects such as extrapyramidal reactions, sedation, emotional blunting, sexual dysfunction, metabolic syndrome, and orthostatic hypotension (Goodnic#
et al, 1 8; ,atham -., 2002)!

0*

4.3.2-/lternati&e drug treatments: 7en!odia!epines: 4igh potency benzodiazepines such as clonazepam and lorazepam are commonly used as an alternative to or in combination ith antipsychotics hen patients are experiencing acute mania, agitation, anxiety, panic, and insomnia, or cannot take mood stabilizers (e!g!, during the first trimester of pregnancy) (American
Psychiatric Association,2002; Goldberg et al,1 )!

Benzodiazepines cause minimal adverse effects compared to antipsychotics, and at higher doses, rapidly sedate agitated patients (Goldberg et al,1
),

Benzodiazepines can

cause central nervous system depression, sedation, cognitive and motor impairment, dependence, and ithdra al reactions! )elative contraindications for long$term therapy ith benzodiazepines are drug or alcohol abuse or dependency! Ghen no longer re'uired, benzodiazepines should be gradually tapered and discontinued to avoid ithdra al symptoms (Di&iro et al, 2008)! /ntidepressants: .ntidepressants are routinely added for the treatment of acute depression, but some studies have reported that specific classes such as the tricyclic antidepressants can carry an increased risk of inducing mania in bipolar I disorder and possibly cause rapid cycling (American Psychiatric Association,2002; Goldberg et al,1
)!

-ome guidelines recommend avoiding antidepressants in the treatment of bipolar depression or limiting their use to brief intervals, but recent evidence suggests that the coadministration of mood stabilizers can reduce the risk of antidepressant induced s itching ("ec# et al, 200/)! In general, the antidepressant should be gradually ithdra n 9 to 2 months after remission, and the patient maintained on a moodstabilizing agent (+achs et al, 2000), &or patients ith recurrent depressive episodes, long$term ad/unctive treatment ith antidepressants can be re'uired to avoid relapses, particularly in bipolar II disorder
(American Psychiatric Association,2002; Goldberg et al,1 )!

)alcium channel antagonists: :alcium channel antagonists inactivate voltage$ sensitive calcium channels, thus inhibiting neurotransmitter synthesis and release and neuronal signal transmission (Man$i et al, 2000; Goodnic# et al, 1
8)!

5imodipine, a dihydropyridine, can be more effective than verapamil for rapid$cycling bipolar disorder because of its anticonvulsant properties, high lipid solubility, and good penetration into the brain (American Psychiatric Association,2002; Goldberg et al,1
Goodnic# et al, 1 8)! ; Man$i et al, 2000;

02

:alcium channel blockers are generally ell tolerated, and the most common adverse effects are bradycardia and hypotension! #he lo teratogenic effects of these agents can make them a preferable choice over lithium or anticonvulsants during pregnancy and breastfeeding (Goodnic# et al, 1
8)!

9-E&aluation of therapeutic outcomes:

#he establishment and maintenance of a therapeutic alliance ith a clinician is essential in monitoring a patientJs psychiatric status and safety3 enhancing treatment adherence, promoting good nutrition, sleep, and exercise, identifying stressors, recognizing ne mood episodes, and minimizing adverse reactions and drug interactions (!orrey, "nable,
2002)!

Datients

ho have a partial response or nonresponse to established bipolar therapies

should be reassessed for an accurate diagnosis, concomitant medical or psychiatric conditions, and medications or substances that exacerbate mood symptoms! 5onadherence to medication treatment, delusional symptoms, alcohol or substance abuse, rapid cycling, or mixed states are often associated ith poorer treatment outcomes! #he evaluation of therapeutic outcomes for bipolar disorder re'uires regular monitoring by a clinician! "ore fre'uent office visits, telephone calls, and intensive outpatient programs are first$line strategies to prevent hospitalization during the acute treatment phase of a manic or depressive episode (American Psychiatric Association,2002)!

1:-;omen .ith "ipolar disorder:

In general, research sho s that than men! In bipolar disorder, hypomania that alternate omen tend to experience more periods of depression omen are more likely to develop the type bipolar II

meaning they never develop severe mania, but instead have milder episodes of ith depression! Gomen are also at higher risk for rapid cycling, hich means having four or more mood episodes in one year (WebMD,2008)! 1:.1-7ipolar disorder drugs and reproduction: "ood stabilizing drugs for bipolar disorder have been linked problems in female hormones! #his condition puts ith reproductive

omen, specifically polycystic ovarian syndrome, a problem related to omen at risk for infertility, diabetes, and 0I

possibly heart disease and cancer of the uterus! 4o ever, the condition is treatable ith medications! Before and during pregnancy, omen should not take lithium and other bipolar ill stabilize someone ith

medications, says "ichael .ronson, a clinical psychiatrist and consultant for Geb"%! "#he interesting thing is, sometimes pregnancy by itself bipolar disorder! .t other times, it can destabilize them! #he best alternative for someone ho is pregnant, ho is having problems ith depression or mania and cannot be placed on an ade'uate dose of medication, is using (:# (electroconvulsive therapy)! It's very effective and it's safe!" (WebMD,2008)! 1:.2-7ipolar disorder drugs and menopause: #he hormone fluctuations of perimenopause and menopause can cause mood disorders in any oman not /ust those ith bipolar disorder! 4o ever, for those already having omen may be troubles ith ma/or depression, bipolar, or anxiety disorders there usually is an increase in symptoms during this time! (specially during perimenopause, especially vulnerable to depressive symptoms because of declining estrogen levels, %uring menopause, hormone therapy may help! . change in antidepressant or mood stabilizing drug also may be the ans er (WebMD,2008)!

11-Related ne.s:
11.1- tudy sho.s symptoms of "ipolar disorder may continue in adulthood: Cct! 2, 9++; :hildren ho are diagnosed ith bipolar disorder can continue to suffer

from the disease as they develop into young adults! Barbara 8eller, and her colleagues at Gashington Hniversity follo ed a sample of children diagnosed ith pediatric bipolar disorder into adulthood! Beginning in 0<<* to 0<<;, the researchers examined 00* children diagnosed bipolar disorder ith

ith an average age of 00! .t the beginning of the study and again

during nine follo $up visits conducted over eight years, the children and their parents ere intervie ed separately about their symptoms, diagnoses, daily cycles of mania and depression, and interactions ith others! %uring the eight$year follo $up, the researchers found that the children's first, second, and third episodes of mania included psychosis and daily cycling bet een mania and 0;

depression for long periods of time! "any of them recovered from these episodes, but about I=, of them relapsed! .fter the follo $up period, 8eller and her colleagues found that about 11, of those ho had bipolar disorder as children and ho turned 0; by the end of the study period continue to have manic episodes as young adults! =*, of them had substance use disorders, a rate similar to those diagnosed ith bipolar disorder as adults! "#he study provides validation that the illness continues into adulthood in a very large proportion of the children, and unfortunately like adults high rate of substance dependence," says 8eller! #he study concluded that the severity and chronic nature of this disorder highlights the need for a greater effort to ard understanding the neurobiology behind the disease and for developing prevention and intervention strategies! 11.2- tudy sho.s age of dad is a factor in risk of child de&eloping "ipolar disorder: -ept! 9, 9++; . ne study suggests that children born from older fathers are at ith the disease, they have a

increased risk of developing bipolar disorder! Cverall, children born to fathers in their mid$*+s and older ere found to have a =I,

higher risk for bipolar disorder than children born to dads in their early 9+s! #he risk of developing the mood disorder before the age of 9+ bet een the ages of 9+ and 91! .ccording to the 5ational Institute of "ental 4ealth, about *!I million .merican adults have bipolar disorder, a serious mental illness characterized by dramatic, episodic mood s ings! Ghile the mood disorder tends to run in families, suggesting a genetic link, little else is kno n about the causes of bipolar disorder! Clder maternal age as associated ith a slight, but nonsignificant, overall increase in as roughly 9!*$times

greater for children born to men age *+ and older than for children born to men

risk, but no association diagnosis before age 9+!

as seen bet een maternal age and the risk for a bipolar

#he fact that paternal age appears to be a more important risk factor for bipolar disorder than maternal age suggests that genetic mutations in sperm may be to blame! "en add 0<

more mutations to the gene pool than

omen because their reproductive cells continue

to divide throughout their lives! Gomen have only about 9= divisions in the cells that produce their eggs, and these divisions occur before birth, "ore divisions mean more potential mutations or %5. damage that could be driving the increased risk for bipolar disorder and other genetically influenced mental disorders! 11.3- tudy sho.s family connections for "ipolar disorder and schi!ophrenia: Lan! 0*, 9++< #he largest study ever to track bipolar disorder and schizophrenia cause! &or more than a century the psychiatric community has debated hether schizophrenia ithin

families offers evidence that the t o psychiatric disorders share a common genetic

and bipolar disorder ere t o distinct disorders or ere more connected! Cver the course of their illnesses, many patients experience similarities in certain symptoms characteristic of both, such as manic mood s ings in bipolar disorder and psychosis in schizophrenia! )ecent genetic studies suggest a common genetic cause for the t o conditions! But earlier studies in families have not supported this conclusion, finding no increase in bipolar disorder in family members of schizophrenics and vice versa (WebMD,2008)!

9+

12-References:
.merican Dsychiatric .ssociation! %iagnostic and -tatistical "anual of "ental %isorders, &ourth (dition, #ext )evision! Gashington, .merican Dsychiatric .ssociation, 9+++@=;961+0! .merican Dsychiatric .ssociation! Dractice 8uideline for the #reatment of Datients ith Bipolar %isorder ()evision)! .m L Dsychiatry 9++930*<@06*+! :alabrese L), -helton "%, )apport %L, et al! >ong$term treatment of bipolar disorder ith lamotrigine! L :lin Dsychiatry 9++932=(-uppl0+)@0;699! %iDiro L!, #albert )!, Pee 8!, "atzke 8!, Gells B!, Dosey >!, Dharmacotherapy . Dathophysiological .pproach, seven edition, 9++;! 8oldberg L&, 4arro ", eds! Bipolar %isorders@ :linical :ourse and Cutcome! Gashington, %:@ .merican Dsychiatric Dress, 0<<<! 8oodnick DL, ed! "ania@ :linical and )esearch Derspectives! Gashington, %:@ .merican Dsychiatric Dress, 0<<;! 4urley -:! >amotrigine update and its use in mood disorders! .nn Dharmacother 9++93=2@;2+6;I=! Ludd >>, .kiskal 4-! #he prevalence and disability of bipolar spectrum disorders in the H!-! population@ )e$analysis of the (:. database taking into account sub threshold cases! L .ffect %isord 9++=3I=@09=60=0! Qeck D( Lr!, 5elson (B, "c(lroy ->! .dvances in the pharmacologic treatment of bipolar depression! Biol Dsychiatry 9++=3*=@2I062I<! "ahmood #, -ilverstone #! -erotonin and bipolar disorder! L .ffect %isord 9++0322@06 00! "an/i 4Q, Bo den :>, Belmaker )4, eds! Bipolar "edications@ "echanisms of .ction! Gashington, %:@ .merican Dsychiatric Dress, 9+++! Darker &, 8ibson 5., Brotchie 4, et al! Cmega$= fatty acids and mood disorders! .m L Dsychiatry 9++2302=@<2<6<I;! Derlis )4, Gelge L., Oornik >., et al! .typical antipsychotics in the treatment of mania@ a meta$analysis of randomized, placebo$controlled trials! L :lin Dsychiatry 9++232I@*+<6*02! -achs 8-, Qoslo :>, 8haemi -5! #he treatment of bipolar depression! Bipolar %isord 9+++39@9*2692+! 90

#aylor >, &arone -O, #suang "#! &amily, t in, and adoption studies of bipolar disease! :urr Dsychiatry )ep 9++931@0=+60==! #orrey (&, Qnable "B! -urviving "anic %epression@ . "anual on Bipolar %isorder for Datients, &amilies, and Droviders! 5e Pork@ Basic Books, 9++9! Geb"% "edical )eference ith #he :leveland :linic@ "Bipolar %isorder ("anic %epressive %isorder)!" Geb"% .ssess Dlus@ Bipolar %isorder .ssessment! 5ational Institute for "ental 4ealth@ "-tep$B% GomenJs -tudies!" "assachusetts 8eneral 4ospital Bipolar :linic R )esearch Drogram! "edicine5et!com@ "Bipolar %isorder ("ania)!" Geb"% "edical )eference ith #he :leveland :linic@ "(ffects of Hntreated %epression!" .merican Dsychiatric .ssociation@ "Dractice 8uideline for the #reatment of Datients Gith Bipolar %isorder!" )evie ed by .mal :hakraburtty, "% on Luly 99, 9++;! Patham >5! #he role of novel antipsychotics in bipolar disorders! L :lin Dsychiatry 9++932=(-uppl=)@0+601!

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