OVERVIEW OF MOOD DISORDERS

1. OVERVIEW OF MOOD DISORDERS Dr. H. Gandy, MD, FRCPC Children’s Hospital of Eastern Ontario April 24, 2007

2. Mood Disorders Review • Types of Mood Disorders • Epidemiology • Clinical Symptoms and DSM-IV diagnoses • Etiology of Mood Disorders • Treatments • Questions

3. Mood disorders overview Types of mood disorders • Major Depression • Bipolar affective disorder (BAD I, BAD II, Cyclothymic Disorder • Dysthymic Disorder • Seasonal affective disorder • Substance induced affective disorder • Mood disorder secondary to general medical condition

4. Mood disorders overview Epidemiology of depression • Major depression typical onset is the mid-20s.the peak annual prevalence occurred in ages 15 to 25 years. • NIMH research indicates depression onset is occurring earlier than in past decades. • Depression in youth may predict more severe illness in adulthood. • Lifetime prevalence of major depressive episode is 12.2% • Approximately 8% of adults will experience major depression at some time in their lives. • Major depression is more common in women than men. • Prevalence of major depression can be related to having a chronic medical condition or unemployment. • Married people have the lowest prevalence of depression. • Worldwide, major depression is the leading cause of years lived with disability and the fourth leading cause of disability adjusted life years.

5. Mood disorders overview Epidemiology of bipolar disorder • Weighted lifetime prevalence rate is 2.2% • Younger age, low income, lifetime anxiety disorder and presence of substance use disorder in the past 12 months were significantly associated with the presence of a bipolar disorder diagnosis. • A lifetime history of anxiety disorder was reported by 52% of those diagnosed with bipolar disorder. • Both panic disorder and agoraphobia were more frequent among women compared with men diagnosed with BAD. • The mean age of onset of illness was 22.5 years the standard deviation of 12 years • It is estimated over 500,000 Canadians likely suffer from bipolar disorder

6. Mood disorders overview Epidemiology of Dysthymia • Prevalence in general practice setting 5.1%. • 90% of those diagnosed had at least one co-morbid psychiatric disorder. • Patients with dysthymia are more likely to have worse health status, worry more about their health, report levels of pain that impair their function, have higher depression scores, lower social role function scores, lower social adjustment scores and lower coping ability. • More children of people with dysthymia meet criteria for one or more childhood psychiatric disorders. • People with dysthymia used a greater proportion of health and social services, had higher per person annual health-care costs.

7. Mood disorders overview Major depression-clinical symptoms • Sad or empty mood • Feelings of hopelessness, pessimism • Feelings of guilt, worthlessness, helplessness • Loss of interest or pleasure in activities that were once enjoyed • Decreased energy, fatigue, being “slowed down” • difficulty concentrating, remembering, making decisions • Insomnia, early-morning awakening or oversleeping • Appetite and/or weight loss or overheating and weight gain • Thoughts of death or suicide; suicide attempts • Restlessness, irritability • Persistent physical symptoms that do not respond to treatment such as headaches, digestive disorders and chronic pain

8. Mood disorders overview • S leep • I nterest • G uilt • E nergy • C oncentration • A ppetite • P sychomotor • S uicide

9. Mood disorders overview Major depression-DSM-IV diagnosis • Depressed mood or loss of interest or pleasure in daily activities for at least a two week period • Mood must represent a change from persons normal mood • Major depression cannot be diagnosed if depressed mood is caused by substances or a general medical condition. • At least five of the following symptoms must be present for a two-week period: • Abnormal depressed mood • Abnormal loss of interest and pleasure • Appetite or weak disturbance • Sleep disturbance • Activity disturbance • Abnormal fatigue or loss of energy • Abnormal self reproach or guilt • Abnormal concentration or indecisiveness • Abnormal morbid thoughts of death or suicide

10. Mood disorders overview Bipolar Affective Disorder classification-DSM-IV • Bipolar I disorder • One or more manic or mixed episodes, usually accompanied by major depressive episodes • Major manic episode may include delusional ideation and hallucinations. (Bipolar with psychotic features) • Bipolar II disorder • One or more major depressive episodes accompanied by at least one hypomanic episode. • No evidence of psychotic features • Cyclothymic disorder • Chronic, fluctuating mood disturbance involving numerous periods of hypomanic symptoms and numerous periods of depressive symptoms. • Symptoms may be severe but no suicidal ideation or incapacitation

11. Mood disorders overview Bipolar affective disorder-clinical symptoms-mania • Abnormal or excessive elation • unusual irritability • Decreased need for sleep • Grandiose ideation • Increased talking • racing thoughts • Increased sexual desire • Markedly increased energy • Poor judgment • Inappropriate social behavior

12. Mood disorders overview Bipolar affective disorder – DSM-IV criteria Manic episode: • A distinct period of abnormally and persistently elevated, expansive or irritable mood lasting at least one week • During this period of mood disturbance three or more of the following symptoms have persisted: • Inflated self-esteem or grandiosity • Decreased need for sleep • More talkative than usual • insomnia or hypersomnia nearly every day • psychomotor agitation • Flight of ideas or subjective experience that thoughts are racing • Distractability • Increased goal directed activity and/or excessive involvement in pleasurable activities that have a high potential for negative consequences

13. Mood disorders overview Dysthymia-clinical symptoms • A chronically depressed mood that occurs most of the day or days for at least two years. • No major depressive episode has been present during the first two years of the disturbance. • The disturbance is not better accounted for by chronic major depression or major depressive disorder in partial remission. • There has never been a manic episode. • The disturbance does not occur exclusively during the course of a chronic psychotic disorder • The symptoms are not due to the direct effects of a substance or a general medical condition • The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.

14. Mood disorders overview Dysthymia-DSM-IV criteria • A depressed mood for most of the day, for more days than not, as indicated either by subjective account or observation by others, for at least two years. In children and adolescents the duration must be at least one year. • The presence of two or more of the following: • Poor appetite or overeating • insomnia or hypersomnia • Low-energy or fatigue • low self-esteem • poor concentration /difficulty making decisions • feelings of hopelessness • During the two-year period the person has never been without the symptoms for more than two months at a time.

15. Mood disorders overview Etiology of mood disorders - Biological factors Biogenic amines • Norepinephrine - down regulation of beta adrenergic receptors and drug response • Serotonin – decrease in serotonin receptors after long-term exposure to drugs • Dopamine – activity may be reduced in depression and increased in mania Other neurochemical factors • GABA - amino acid neurotransmitter implicated in depression • Adrenal axis – correlation between hypersecretion of cortisol and depression • Thyroid axis – blunted release of TSH to infusion of TRH seen in depression • Growth hormone – blunted sleep induced stimulation of GH release in depression Sleep abnormalities – delayed sleep onset, shortened REM latency in depression Kindling – in temporal lobes involved in pathophysiology of bipolar disorder Circadian rhythms – sleep deprivation and transient clinical improvement in depression. Light level changes in seasonal affective disorder Neuroimmune regulation – cortisol axis disruption may affect immune status Brain imaging – enlarged cerebral ventricles in BAD, smaller caudate nuclei in depression.

16. Mood disorders overview Etiology continued Neuroanatomical considerations – limbic system, basal ganglia, hypothalamus Genetic factors • Family studies – 1st degree relatives are 8 to 18 times more likely than controls to have BAD, 2 to 10 times more likely in depression. • Adoption studies – biological children of affected parents remain at increased risk even if reared in non-affected adoptive families. • Twin studies – concordance rate for BAD in monozygotic twins is up to 90% • Linkage studies – chromosomes 5, 11 and X have been implicated particularly in BAD Psychosocial factors • Life events and environmental stress – stress, family functioning, early loss • Premorbid personality factors – dependent, obsessional, hysterical personalities at greater risk for depression • Psychodynamic factors – object loss, depressive position, aggression turned inwards, incompleteness and despair • Learned helplessness • Cognitive theory – cognitive distortions

17. Mood disorders overview Medical causes of depressive symptoms Neurological • Cerebrovascular disease • Dementia • Epilepsy • Infections • Multiple sclerosis • Neoplasms • Parkinson’s disease • Wilson’s disease • hydrocephalus

18. Mood disorders overview Medical causes of depressive symptoms Endocrine • Adrenal • Menses related • Postpartum • Thyroid disorders Infectious and inflammatory • AIDS • Chronic fatigue syndrome • Mononucleosis • Pneumonia • Lupus • tuberculosis

19. Mood disorders overview Medical causes of depressive symptoms Miscellaneous medical • Cancer • Cardiopulmonary disease • Porphyria • Vitamin deficiencies

20. Mood disorders overview Pharmacological causes of depressive symptoms • Analgesics and anti-inflammatories - ibuprofen • Antibacterial’s – ampicillin, metronidazole • Antihypertensive’s – beta blockers, clonidine, reserpine • Antineoplastics – bleomycin, vincristine • Neurological and psychiatric – amantadine, carbamazepine, Ritalin • Steroids and hormones – corticosteroids, oral contraceptives, prednisone

21. Mood disorders overview Seasonal affective disorder • A seasonal pattern which can be applied to major depressive episodes and bipolar I, bipolar II disorders • A regular temporal relationship between the onset of depressive episodes and a particular time of year (not seasonal related psychosocial stressors) • Full remissions also occur at a characteristic time of year • In the last two to four years major depressive episodes have occurred that demonstrate the temporal seasonal relationship to findings above • Episodes substantially outnumber non-seasonal depressive episodes that may have occurred over a lifetime.

22. Mood disorders overview Postpartum depression • Major depressive, manic or makes episode or brief psychotic disorder associated with postpartum onset. • Onset of episode is within four weeks postpartum

23. Mood disorders overview Treatments Psychosocial therapies Psychodynamic psychotherapy (Freud, Kohut) • Involves ego regression in the service of promoting personality change through understanding of past conflicts and achieving insight into various psychological defenses. Involves confronting defenses and full or partial analysis of transference and resistance. Cognitive behavioral therapy (Adler, Beck) • Involves analysis of distorted thinking leading to dysphoria due to learned negative views of self, others and world. Provides symptomatic relief through alteration of target thoughts, identifying self-destructive cognitions. Involves recording and monitoring cognitions, correcting distorted schemas with logic and experimental testing including homework.

24. Mood disorders overview Cognitive distortions • All or nothing thinking • Overgeneralization • Mental filter • Disqualifying the positive • Jumping to conclusions

25. Mood disorders overview Cognitive distortions • Magnification and minimization • Emotional reasoning • “Should” statements • Labeling • Personalization

26. Mood disorders overview • Psychosocial therapies cont’d • Interpersonal psychotherapy (Meyer, Sullivan, Klerman, Weissman) • Depression is a result of impaired interpersonal relations involving absent or unsatisfactory social bonds. • Provide symptomatic relief through resolution of current interpersonal problems improving interpersonal communication skills. • Therapy involves clarifying and managing maladaptive relationships and learning new ones through communication and social skills training.

27. Mood disorders overview Treatment Pharmacotherapy – depression • antidepressants • SSRI’s – Prozac, Paxil, Zoloft, Celexa, Luvox, Cipralex • SNRI’s – Effexor, Remeron • TCAs – amitriptyline, desipramine, Clomipramine • RIMA’s - Moclobemide • MAOI’’s – Phenelzine, Tranylcypromine Pharmacotherapy – bipolar disorder • Lithium carbonate • Epival/valproic acid • Carbamazepine • Olanzapine,Quetiapine, risperidone • Lamotrigine • Topiramate

28. Mood disorders overview SSRIs • Best evidence of efficacy in the pharmacological treatment of depression • First-line treatment in moderate to severe depression • 3 to 8 weeks required until full therapeutic effect • One year maintenance therapy typically recommended • Well tolerated, safe in overdose, simple prescribing regimens • Few drug interactions – can be used in combination with other classes of medications with some exceptions. • Up to 80% of adults will respond to first medication But… • Significant side effects frequently underreported • Withdrawal syndromes reported • May contribute to or worsen suicidal ideation in first four weeks of treatment • Only 40 to 50% response rate in children and adolescents(? Safety)

29. Mood disorders overview SSRIs/SNRIs Common side effects include: • Fatigue, headache, dry mouth, blurred vision, nausea, diarrhea, urinary hesitancy, tremor, sweating, vivid dreams, sexual dysfunction • Rare side effects include serotonin syndrome, akathesia,? Suicidal ideation/behavior, extrapyramidal symptoms

30. Mood disorders overview Tricyclic antidepressants • Second or third line drug treatment for depression • Good evidence of efficacy in adults. No evidence of efficacy in children and adolescents. • Same side effect profile as SSRIs plus: • Cardiac arrhythmias and conduction issues (prolonged QT interval) • Lowers seizure threshold • Significantly more intense side effects than SSRIs • Dangerous/lethal in overdose • Several significant drug-drug interactions

31. Mood disorders overview RIMAs • Selective blocker of MAOI A (80%) found mostly in the brain thus dietary restrictions not required • Reversible in that they inhibit the enzyme for a time, but eventually detach, allowing the enzyme to function once more • Only one drug in this class available in Canada • Limited evidence of efficacy in treatment of depression. • Some evidence of efficacy in treatment of anxiety disorder • May has some advantages in the treatment of atypical depression • Not considered first line treatment

32. Mood disorders overview MAOIs Block enzymatic degradation of monoamines including tyramine • Increased levels of tyramine can cause sudden increases in blood pressure leading to hypertension, strokes and MIs This is prevented by restricting dietary tyramine Foods to be avoided: • aged foods • alcoholic beverages (especially chianti, sherry, liqueurs, and beer) • alcohol-free or reduced-alcohol beer or wine • anchovies • bologna, pepperoni, salami, summer sausage, or any fermented sausage • caviar • cheeses (especially strong or aged varieties), except for cottage and cream cheese • chicken livers • fermented foods • figs (canned) • fruit: raisins, bananas (or any overripe fruit) • meat prepared with tenderizers; unfresh meat; meat extracts • smoked or pickled meat, poultry, or fish • soy sauce

33. Mood disorders overview Lithium Carbonate • Considered gold standard in treatment of mania and maintenance therapy for BAD • Lithium enhances the uptake of norepinephrine and serotonin into the synaptosomes, thus reducing their action. • It reduces release of norepinephrine from synaptic vesicles and inhibits production of cyclic AMP. • In humans, lithium alters the excitability of the CNS as measured by cortical evoked potentials • Can be used in combination with other antimanic drugs. • Narrow therapeutic window thus plasma concentration monitoring is essential

34. Mood disorders overview Lithium Carbonate • Initial workup includes CBC, lytes, BUN, Cr, (sometimes 24 hr creatinine clearance) glucose, ECG, TSH • Therapeutic range 0.5 to 1.5 mmol/L. Serum concentrations over 2 mmol/L are considered toxic Common side effects include: • Anorexia, nausea, vomiting,diarrhea,thirst, tremor, ataxia, weakness, restlessness, polyuria, rash and acne • Worsening of sluggishness, drowsiness, lethargy, coarse hand tremor or muscle twitchings, loss of appetite, vomiting, and diarrhea suggest onset of toxicity.

35. Mood disorders overview Anticonvulsants • Epival, Valproic Acid, carbamazepine • May be used in combination with lithium • Some require blood level monitoring • Evidence for effectiveness as a first line agents • Less value in maintenance therapy • Thrombocytopenia, leukopenia must be monitored • With Epival: growing concerns about polycystic ovarian disease • Lamotrigine showing promise particularly for preventing depression in BAD • Lamotrigine carries risk for Stevens-Johnson syndrome • Topirmate is weight neutral or causes some weight loss

36. Mood disorders overview Atypical antipsychotics • Olanzapine showing promise as first-line agent for both acute episodes of mania and in maintenance therapy • May be used in combination with lithium or anticonvulsants • Low incidence of EPS but other side effects significant including: • Weight gain • Glucose metabolism abnormalities including DKA • Dyslipidemias • Hyperprolactinemia • Unknown if tardive dyskinesia represents a significant long-term side effect

37. Mood disorders overview Physical treatments • ECT – treatment resistant depression catatonia, psychotic depression • Repetitive transcranial magnetic stimulation – efficacy similar to ECT – no GA required and fewer post procedure side effects • Vagal nerve stimulation – deep brain stimulation for treatment refractory cases • Direct Deep Brain Stimulation • Light therapy – for SAD, specific wavelengths shown to be most effective

38. Mood disorders overview Hospitalization • Form 1 criteria – harm to self, harm to others, severe psychosis, mania or catatonia, unable to care for self in the community • Treatment resistant cases • Poor psychosocial supports • Complex cases and/or complex treatment regimens • Delivery of ECT • Medically compromised cases

39. Mood disorders overview Questions?