The key differential diagnoses for manic episode, according to DSM-IV, are mood disorder due to a general medical condition, substance-induced mood disorder, hypomanic episode, mixed episode, and attention-deficit/hyperactivity disorder. Mood disorder due to a general medical condition should be diagnosed if the patient has a mood disturbance that is judged, based on history (H/O), laboratory findings, or physical examination, to be the direct physiologic result of a general medical condition. Examples of medical conditions that may cause manic symptoms include multiple sclerosis, Cushing’s syndrome, and brain tumor. Onset of a first manic episode after age 50 years is an indication to consider a diagnosis of either mood disorder due to a general medical condition or substance-induced mood disorder. A substance-induced mood disorder is distinguished from a manic episode based on the finding that a substance—whether a medication, a recreational drug, or a toxin, is etiologically related to the mood disturbance. Note that manic symptoms precipitated by antidepressant therapy—medication, light therapy, or electroconvulsive therapy—should be diagnosed as substance-induced mood disorder, not mania. Hypomanic episode should be diagnosed if excitement symptoms are present but are not sufficient to meet the criteria for manic episode. Mixed episode should be diagnosed if the criteria for both manic episode and major depressive episode (MDE) are met nearly every day for at least 1 week. 10
Attention-deficit/hyperactivity disorder (ADHD) and mania have several symptoms in common, including excessive psychomotor activity, impulsivity, impaired judgment, and denial of pathology. ADHD is discerned from manic episode by a chronic rather than episodic course, a lack of clear onsets and offsets of mood disturbance, the absence of abnormally elevated mood or psychotic features, and a history of (H/O) early-childhood onset (prior to the age of 7 years). Although it is important to be able to differentiate the two, it is important to note that ADHD can coexist with bipolar disorder. Eating disorders, panic attacks, borderline personality disorder, ADHD, and compulsive behavior may be signs of bipolar disorder among other psychologic syndromes. 11
A mixed episode consists of at least 1 week during which criteria for both a manic episode and a major depressive episode (MDE) are met nearly every day. Mood tends to alternate rapidly between euphoria, sadness, and irritability. Symptoms must be sufficient to impair social or occupational functioning or to require hospitalization. Alternatively, hospitalization must be required. Common symptoms include agitation, appetite disturbance, insomnia, psychosis, and suicidal ideation. Relative to manic episodes, mixed episodes are more commonly characterized by dysphoria and disorganization; therefore, patients experiencing mixed episodes may be more likely to seek help than those experiencing purely manic episodes. Mixed episodes may be more common in younger and older persons with bipolar disorder and may be more likely to occur in male than in female individuals. 16
The peak age of onset for bipolar disorders is adolescence through early 20s. Approximately one fourth of first episodes occur before the age of 20 years. Onset of a first manic episode after the age of 40 years should signal substance use or a general medical condition as the possible cause of the symptoms. Seasonal variation of episodes have been noted in some patients. Depression appears to be more common in the spring, specifically, March through May, and in the autumn, specifically, in September through November. Manic episodes appear to be more common in the summer months. 3
Although estimates vary, data from community samples estimate the lifetime prevalence of bipolar I disorder (BPD I) at up to 1.6%. The lifetime prevalence of bipolar II disorder (BPD II) alone is approximately 0.5%. There is no apparent differential incidence of bipolar disorder based on race or ethnicity. However, there is some evidence of a greater tendency to overdiagnose schizophrenia instead of bipolar disorder in some ethnic groups. BPD I is believed to be equally common in men and women. BPD II, on the other hand, may be more common in women. In men with bipolar disorder, the first episode is likely to be manic; in women, the first episode is likely to be depressive. 1
Bipolar I disorder (BPD I) is recurrent in more than 90% of cases. Approximately 60% to 70% of manic episodes occur immediately before or after a major depressive episode (MDE). Each individual tends to develop a pattern in which manic and depressive episodes precede and follow each other. In the absence of treatment, individuals with BPD I will suffer an average of 4 episodes in a 10-year period. In the case of bipolar II disorder (BPD II), approximately 60% to 70% of hypomanic episodes occur immediately before or after an MDE. Both BPD I and BPD II show tendencies to run in families, although this tendency is more evident in BPD I. First-degree biological relatives of individuals with BPD I have increased rates of BPD II and major depressive disorder (MDD), and twin and adoption studies provide convincing evidence of genetic predisposition. Some studies also suggest that first-degree relatives of individuals with BPD II have increased rates of BPD II, BPD I, and MDD. 2
In the clinical setting, bipolar depression can be difficult to distinguish from unipolar depression. In a recent study, 48 consecutively admitted patients diagnosed with bipolar I disorder (BPD I) (n=44) or schizoaffective disorder, bipolar type (n=4), were systematically interviewed using strict DSM-IV criteria, and their charts were reviewed to confirm preadmission diagnoses. In this sample, 43% of the patients (19 of 44 available patients), were found to have previously undiagnosed bipolar disorder; all had previously been believed to have unipolar major depression. It took an average of 7.5 years to establish an accurate diagnosis for these patients. Although some have criticized these criteria for being too narrow, this study shows that strict application of DSM-IV criteria can help clinicians distinguish unipolar depression from bipolar disorders. This slide summarizes some factors that may help differentiate these diagnoses. Evaluating patients’ interepisode personalities can be particularly helpful. Hyperthymic temperament is characterized by a hypomanic state at baseline; these patients have been described as cheerful, extroverted, and habitually short sleepers. Patients with cyclothymic personalities also have hypomanic baseline personalities, but their hypomania alternates with mildly depressive episodes that do not meet criteria for major depressive episode (MDE). The bottom line is that bipolar disorder should always be considered in the differential diagnosis of patients with depression. H/O = history of. 17
ByDr. Maged Al AdrousyLecturer of psychiatry- Cairo university
introduction Bipolar disorder is an episodic, potentially life-long, disabling disorder that can be difficult to diagnose. known as Manic Depression, Results in pathological mood swings from mania to depression, These mood swings occur spontaneously.
History Bipolar Disorder 200 CE First reports 1654 Jean Pierre Falret “folie circulaire" (circular insanity) Familial illness 1913 Emil Kraepelin Manic - Depressive 1930’s ECT first used 1949 Lithium first used 1950 Chlorpromazine first used 1952 Genetic link recognized 1980 Bipolar Disorder term adopted 1995 Depakote approved for BP 2003 First atypical approved for BP
Types of Mood Disorders 10% 2% DSM IV 2% MDD Major Depressive Disorder BP I Dysthymic Disorder BP II Bipolar Disorder Type I NOS Bipolar Disorder Type II 86% Cyclothymic Disorder NOS Mixed Phase Rapid Cyclers 33% MDD BP I Bipolar Spectrum (BPS) 50% BP II BPS 15% 2%
Bipolar disorder is a cyclical mood disorder Abnormally elevated mood or irritability alternates with depressed mood bipolar I – at least one manic or mixed episode bipolar II – at least one major depressive episode and at least one hypomanic episode Cyclothymia = hypomania with “minor” depression “Bipolar spectrum” = Depression + other complexities Bipolar NOS or Mood DO NOS
Structure of a Recurrent Illness Precipitant EpisodeUnderlying illness
Spectrum of Illness CourseEpisodic UnstablePurely episodic course: Radical mood instability:-interepisode stability -’interepisode’ instability-no mixed states -mixed states-infrequent episodes -frequent episodes-good recovery -incomplete recovery-low incidence of complications -high incidence of complications -early onset -stronger genetic loading? Course of illness dictates response strategies for the acute episode
DIAGNOSTIC CRITERIA FOR MANICEPISODES THREE TO FOUR OF THE FOLLOWING CRITERIA ARE REQUIRED DURING THE ELEVATED MOOD PERIOD Highly inflated or grandiose self-esteem Decreased need for sleep, or rested after only a few hours of sleep Pressured speech Racing thoughts and flight of ideas Easy distractibility, failure to keep attention Increased goal-directed activity High excess involvement in pleasurable activities (sex, travel, spending money)General criteria for a manic episode require a period of elevated, expansive,or irritable mood that lasts 1 week or requires hospitalization. A generalmedical condition and substance abuse must be ruled out before thesesymptoms are considered mania.
Manic Episode:Differential Diagnoses Differential diagnosis Consider if . . . Mood disorder due to a Major medical condition present general medical condition First episode at >50 years of age Symptoms in context of intoxication Substance-induced or withdrawal mood disorder History of treatment for depression Mood disturbance not severe Hypomanic episode enough to require hospitalization or impair functioning Mixed episode Manic episode and MDE in 1 week
Manic Episode:Differential Diagnoses (cont.) Differential diagnosis Consider if . . . AD/HD Early childhood mood disturbance onset Chronic rather than episodic course No clear onsets and offsets No abnormally elevated mood No psychotic features American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). 4th ed. 1994.
Major Depressive Episode:DSM-IV Criteria Depressed mood and/or loss of interest or pleasure ≥ 2 weeks duration Associated symptoms Physical: insomnia/hypersomnia, appetite/weight change, decreased energy, psychomotor change Psychological: feelings of guilt or worthlessness, poor concentration/indecisiveness, thoughts of death/suicidal intentions (SI)
…and ≥4 of the following symptoms Physical Psychological Sleep disorder Low self Appetite change esteem/guilt Poor concentration/ Fatigue indecisiveness Psychomotor Thoughts of death/SI retardation
Mixed Episode: DiagnosticCriteria Criteria met for both manic episode + MDE for ≥1 week Symptoms Are sufficient to impair functioning or Necessitate hospitalization or Are accompanied by psychotic features
Epidemiology Peak age of onset: adolescence through early 20s Onset of first manic episode after age 40 years is “red flag” to consider substance use or general medical condition Lifetime suicide rates range from 10% to 15% Seasonal variation Depression more common in spring and autumn Mania more common in summer
Bipolar Disorders: Epidemiology Characteristics BPD I BPD II Course Recurrent in >90% Hypomanic episodes in of cases BPD II immediately precede or follow MDEs in 60% to 70% of cases First-degree First-degree relatives Familial pattern relatives have may have increased increased rates of rates of BPD I, BPD II, BPD I, BPD II, and and MDD MDD
Diagnostic Dilemmas:Unipolar Versus Bipolar No evidence of hypomania, Unipolar cyclothymia, hyperthymic personality, or family history of BPD ≥1 manic episode BPD I Recurrent major depression with BPD II hypomania and/or cyclothymic temperament Recurrent major depression without BPD NOS spontaneous hypomania but often with hyperthymic temperament and/or family history of BPD
CYCLOTHYMIC DISORDER Cyclothymic disorder is a recurrent, chronic, mild form of bipolar disorder in which mood typically oscillates between hypomania and dysthymia. If a manic episode or depressive episode is experienced, cyclothymic disorder is not diagnosed. http://www.allaboutdepression.com/cyclothymia/images/graph ic2.gif
CYCLOTHYMIC DISORDER EPIDEMIOLOGY ETIOLOGY The lifetime prevalence of Genetic and familial studies revealcyclothymic disorder is 0.4% to 1%. an association with other mood disordersThe rate appears equal in men and women, although women are usually more likely to seek treatment
CLINICAL MANIFESTATIONS OFCYCLOTHYMIC DISORDER Cyclothymic disorder is a milder form of bipolar disorder consisting of recurrent mood disturbances between hypomania and dysthymic mood. A single episode of hypomania is sufficient enough to diagnose cyclothymic disorder, although most individuals also have dysthymic periods. Cyclothymic disorder is never diagnosed when there is a history of mania, major depressive episode, or mixed episode.
Heritability Evidence for heritability is much stronger for bipolar than for unipolar disorders Specific genetic association has not been consistently replicated
EVIDENCE FOR HERITABILITY OF BIPOLAR DISORDER Family Studies- First degree relatives are 8 to 18 times more likely to have Bipolar I 2 to 10 times to have MDD. Risk is 25% if one parent has illness, and 50% to 75% with both parents affected
FAMILY STUDIES The majority of individuals with bipolar disorder have a positive family history of some type of mood disorder About 50% of all bipolar I patients have at least one parent with a mood disorder
ADOPTION STUDIES Prevalence of bipolar disorder in adopted away offspring corresponds to rates in biological, but not adoptive relatives Twin Studies- Concordance rate in MZ twins is 33 to 90%, in DZ is 5 to 25%
Genetic Polymorphism A functional polymorphism is a genetic variant that appears in at least 1% of a population and alters the biological functioning of the individual Some types of polymorphisms in Mood Disorders Serotonin transporter Serotonin 2A receptor MTHF reductase Catachol -o- methyl tranferase (COMT) Tyrosine hydroxylase Cytochrome P450 metabolism of medications
Biological factors Dysregulation in levels catecholamines (++ levels of dopamine and norepinephrine). -- levels of serotonoine ?? Neuroendocrinal factors:• HPA axis (cortisol hypersecreation) may affect BDNF.• Throid dysfucntion. EEG changes (kindling model) Degenerative structural brain changes.
Psychosocial factors Life time events. Behavioral models . Psychological theories.
Impact of BD Higher rates of mortality from other medical conditions Increased substance abuse risk Lifetime suicide attempt risk (.02% in general populatio Bipolar Disorder Type I – 17% Bipolar Disorder Type II – 24% 90% of completed suicides can be traced back to a Mood Disorder High rates of cognitve defeicets affecting Working memory Sustained attention, Abstract reasoning, Visuomotor skills, Verbal memory, Verbal fluency, Cognitive flexibility
A- psychopharmacology Mood stabilizers Atypical antipsychotics. Benzodiazepines. Channel blockers. Others Combination therapy is more effective than monotherapy
Mood stabilizers Lithium Conventional anti-epileptics as carbamazepine and Na valproate. New anti-epileptics lamotrigene gababentine, and topiramate
What Exactly Is a MoodStabilizer? • Some authorities suggest 2 out of 3 of the following properties: – Antimanic, antidepressive, prophylactic • Other experts are more stringent—requiring: – Treatment of acute mania, – Treatment of acute depression, AND – Prevention of recurrent mania and depression – Dosen’t ppt mania or depression. • Lithium remains the gold standard
Lithium Widely recommended treatment for Bipolar Disorder 60-80% success in reducing acute manic and hypomanic states However… issues in non-compliance to take medication, side effects, and relapse rate with its use are being examined in terms of being the best option
Pharmacokinetics: Peak blood levels reached in 3 hrs, fully absorbed in 8 hrs Absorbed rapidly and completely orally Efficacy correlates with blood levels Crosses blood-brain barrier slowly and incompletely Usually taken as a single daily dose
Kinetics Cont. Approx. 2 wks to reach a steady state within the body ½ of oral dose excreted in 18-24 hrs,rest within 1-2 wks Recommended 0.8-1.2 mEq/L, optimum would be 0.6-0.8 mEq/L, with 2 mEq/L displaying toxicity . Monovalent ion not metabolized in liver, excreted by the kidney.
Pharmacodynamics No psychotropic effect on non-Bipolars Affects nerve membranes, multiple receptor systems and intracellular 2nd messenger impulse transduction systems. Interacts with serotonin Potential to regulate CNS gene expression, stabilizing neurons w/ associated multiple gene expression change.
How does a simple ion do all ofthis? Even as a simple ion, it has complex effects on multiple transmitter systems and mood stabilizing attributes This is due to a latter effect reducing a neuron’s response to synaptic input, and therefore stabilizing the membrane
Side Effects and Toxicity Relate to plasma concentration levels, so constant monitoring is key Higher concentrations ( 1.0 mEq/L and up produce bothersome effects, higher than 2 mEq/L can be serious or fatal Symptoms can be neurological, gastrointestinal, enlarged thyroid, rash, weight gain, memory difficulty, kidney disfunction, cardiovascular Not advised to take during pregnancy, affects fetal heart development
Side effects of Li1. GIT symptoms (diarrhea intially)2. Hypokalaemia…….cardiotoxic.3. Polyuria and D.insipius (ADH).4. Tremors.5. Epileptogenic.6. Teratogenic.7. hypothyroidism8. Li toxicity may occure (ttt?)
Na valproate Tab 200mg and 500 mg Dose 50-150 mg% Best for rapid-cycling and acute-mania Actions: through GABA potentiation, Ca channel blockade, Na channel blockade, glutamat antagonist.
Side effects2. Hepatotoxic.3. Wt gain4. Hair loss.5. GIT symptoms.6. Tremors and sedation7. Neural tube defects
carbamazepine Tab 200mg 400 mg Dose 5-15 µg/L Action similar to valproate. Superior to lithium for rapid-cycling, regarded as a second-line treatment for mania Correlation between therapeutic and plasma levels (estimated between 5-10 Mg/L) Side effects:7. Agranulocytosis8. Skin reaction9. Teratogenic10.Liver enzyme induction
Gabapentin Primarily an anti-convulsant, yet also “off label,” or without FDA approval for treatment of Bipolar and many other anxiety, behavioral and substance abuse problems, possibly pain disorders GABA analogue not bound to plasma proteins, not metabolized, few drug interactions Half-Life is 5-7 hours Side Effects include sleepiness,dizziness,ataxia and double vision
Lamotrigine Reported effective with Bipolar, Borderline Personality, Schizoaffective, Post-Traumatic Stress Disorders 98% of administered drug reaches plasma Half-Life is 26 hrs. Inhibits neuronal excitability and modifies synaptic plasticity Side Effects may include dizziness, tremor, headache, nausea, and rash
Topiramate and Tiagabine Two newer anti-convulsants that have potential for use in the treatment of Bipolar disorder
Calcium Channel Blockers Modulate transmitter release & plasticity Most not consistently effective, possibly due to inconsistent uptake into brain Nimodipine reported effective in rapid-cycling, including refractory & ultra-rapid
Atypical Anti-psychotics Risperidone seems more anti-depressant than anti-psychotic Clozapine is effective, yet not readily used due to potential serious side effects Olanzapine is approved for short-term use in acute mania Quatiapine is now approved as a broad spectrum medication in BD esp (Bipolar depression).
Acetylcholinesterase Inhibitors Potentiating the action of acetylcholine may exert relief from mania This potentiation is the result of inhibiting the enzyme acetylcholine esterase
Omega-3 Fatty Acids Obtained from plant or marine sources Known to dampen neuronal signaling transduction systems in a variety of cell systems Being investigated as a treatment for Bipolar Disorder
Three Phases of Treatment Episode Continuation Maintenance0-2 months 2-12 months IndefiniteSymptomatic Functional Stability/adaptive Each phase has specific goals Each phase has specific pharmacological and nonpharmacological rx Treatment must be harmonized across phases
NonpharmacologicTreatments ECT Reports of effectiveness in mania, depression, & refractory mixed states Bilateral generally more effective Continuation ECT may prolong recovery; maintenance? Transcranial magnetic stimulation Psychotherapy : May include cognitive behavioral, psychodynamically oriented, family, couples, interpersonal, and self-help group therapies