Mood Disorders

MOOD DISORDERS : MOOD DISORDERS Fernando Entenza, MD Department of Psychiatry General, Geriatric & Forensic Psychiatrist

Types of Mood Disorders : Types of Mood Disorders Depressive Disorders Major Depressive Disorder Dysthymic Disorder Depressive Disorder NOS Bipolar Disorders Bipolar I Disorder Bipolar II Disorder Cyclothymic Disorder Bipolar Disorder NOS Mood Disorder NOS Due to General Medical Condition Substance-Induced Under investigation Minor depressive disorder Recurrent brief depressive disorder Premenstrual dysphoric disorder

Episode Type = Mood Diagnosis : Episode Type = Mood Diagnosis Episode Type Major Depressive Disorder Bipolar I Disorder Bipolar II Disorder Dysthymic Disorder Cyclothymic Disorder Major Depressive Yes Yes Yes Subthreshold, chronic > 2 years Subthreshold, numerous episodes over 2 years Manic No Yes No No No Hypomanic No Yes Yes No Yes numerous episodes over 2 years Mixed No Yes No No No Never associated with psychosis

PowerPoint Presentation : MAJOR DEPRESSIVE EPISODE

Major Depressive Episode DSM-IV-TR Diagnostic Criterion A : Major Depressive Episode DSM-IV-TR Diagnostic Criterion A > 5 of following sxs > 1 of these * Same 2 wk period Change in functioning Depressed mood * Most of the day, nearly every day Subjective report or observed by others Loss of interest or pleasure * ” ” Weight or appetite change or Nearly every day Significant (5% 1 mo.) Sleep change or Nearly every day - Psychomotor change or Nearly every day Observable (only) Fatigue or loss of energy - Nearly every day - Worthlessness or guilt Exc or inappr Nearly every day Subjective or observed Ability to think or concentrate; indecisiveness Nearly every day Subjective or observed Death or suicide thoughts, plans, or actions Not just fear of dying Recurrent -

Major Depressive Episode DSM-IV-TR Diagnostic Criteria B - E : Major Depressive Episode DSM-IV-TR Diagnostic Criteria B - E B. Symptoms do not meet criteria for a mixed episode C. Clinically significant distress or impairment in social/occupational/other area D. Not due to a direct physiological effects of a substance or a general medical condition E. Not better accounted for by bereavement

Major Depression Symptoms Mnemonic : Major Depression Symptoms Mnemonic S leep I nterest G uilt: E nergy C oncentration A ppetite P sychomotor S uicide SIG: E CAPS Prescription: energy capsules

MANIC & HYPOMANIC EPISODES : MANIC & HYPOMANIC EPISODES

Manic Episode DSM-IV-TR Diagnostic Criteria : Manic Episode DSM-IV-TR Diagnostic Criteria A. > 1 wk period of elevated, expansive, or irritable mood B. > 3 sxs ( > 4 sxs if mood is only irritable) Inflated self-esteem or grandiosity C. Do not meet criteria for mixed episode Decreased need for sleep D. Sufficiently severe to cause marked More talkative than usual or pressured speech impairment in social / occupational functioning Flight of ideas or subjective racing thoughts E. Not due to a direct physiological effects of a substance or general medical condition Distractibility Increase in goal oriented activity or psychomotor agitation Manic-like episodes caused by a somatic antidepressant treatment, (medication, ECT, light therapy) should not count toward a BD diagnosis Excessive pleasurable activities with high potential for painful consequences Any duration if hospitalized

PowerPoint Presentation : Elevated, expansive, or irritable mood Unusually good, cheerful or high; infectious. Unceasing & indiscriminate enthusiasm. Irritable particularly when wishes are thwarted. Labile mood (alterations between euphoria & irritability). Inflated self-esteem or grandiosity From uncritical self-confidence to delusional grandiosity. Giving advise on non-expert matters. Seeking publicity for impractical creation. Having a special relation with God or some public figure. Decreased need for sleep Wakes up several hours earlier than usual, feeling full of energy. When severe, may go for days without sleep and yet not feel tired. More talkative than usual or pressured speech Pressured, loud, rapid, difficult to interrupt. Frequent joking, punning, or amusing irrelevances. Dramatic mannerisms or singing. If irritable, may be marked by complaints, hostile comments, or angry tirades. Flight of ideas or subjective racing thoughts Thoughts may race faster than can be articulated. Flight of ideas (nearly continuous flow of accelerated speech, with abrupt changes from one topic to another). If severe, speech may be disorganized & incoherent. Distractibility Inability to screen out irrelevant external stimuli (i.e. interviewer’s appearance, background noises or conversations, surrounding items/event). Irrelevant thoughts. Increase in goal oriented activity or psychomotor agitation Excessive planning of and participation in multiple activities. Increased sociability. Increased sexual drive, fantasies, and behaviors. May take on multiple simultaneous tasks without regard to completion status or capacity. Interpersonally intrusive, domineering, demanding. Pacing. Holding multiple conversations at once. Prolific writing. Excessive pleasurable activities with high potential for painful consequences Expansiveness + unwarranted optimism + grandiosity + poor judgment = imprudent involvement in pleasurable activities (buying sprees, reckless driving, foolish business investments, sexual behavior unusual for the person), even though these activities may are likely to have painful consequences.

Hypomanic Episode (less severe & remains mostly functional) : Hypomanic Episode ( less severe & remains mostly functional) Hypomanic Episode Duration > 4 days Severity Unequivocal and uncharacteristic change in functioning Mood disturbance and change in functioning are observable by others Not severe enough to cause marked impairment, to need hospitalization, or to have psychotic features Symptoms Same 7 symptoms of mania Same number required > 3 or > 4 if mood is only irritable Manic Episode Duration > 1 week or Any duration if it requires hospitalization Severity Marked impairment or Needs hospitalization or has psychotic features

MIXED EPISODE : MIXED EPISODE

Mixed Episode DSM-IV-TR Diagnostic Criteria : Mixed Episode DSM-IV-TR Diagnostic Criteria A. Criteria for both Manic episode and Major Depressive Episode are met (except for duration) nearly every day during a 1-week period B. Marked impairment in occupational functioning or in usual social activities or relationships with others, or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features C. Not due to the direct physiological effects of a substance (e.g., drug of abuse, medication, or other treatment) or a general medical condition (e.g., hyperthyroidism)

PowerPoint Presentation : Hypomania Mania Depression Depression Subsyndromal (minor) Depression Polarity of Symptoms Thus, Longitudinal Assessment of Bipolar Disorder Is Critical Depression Euthymia Adapted from Frank E, et al. Biol Psychiatry . 2000;48:593-604. Major Depressive Disorder Bipolar II Disorder Bipolar I Disorder Mood Disorders Are Defined By Their Episodes Mania threshold Hypomania threshold Major Depressive threshold

Mixed Episode (Full Criteria) = Bipolar I Disorder : Mixed Episode (Full Criteria) = Bipolar I Disorder Hypomania Mania Depression Depression Subsyndromal (minor) Depression Polarity of Symptoms Mixed Euthymia Adapted from Frank E, et al. Biol Psychiatry . 2000;48:593-604. Mixed Episode Bipolar I Disorder Mania threshold Hypomania threshold

Cyclothymic Disorder = hypomania + minor depression : Cyclothymic Disorder = hypomania + minor depression Hypomania Subsyndromal (minor) Depression Polarity of Symptoms Euthymia Adapted from Frank E, et al. Biol Psychiatry . 2000;48:593-604. Subsyndromal (minor) Depression Subsyndromal (minor) Depression Hypomania Mania threshold Major depressive threshold Hypomania threshold

Mood Disorder Specifiers : Mood Disorder Specifiers Severity/Psychotic features/Remission Melancholic features Atypical features Catatonic features Postpartum Onset

MOOD DISORDER SPECIFIERS : MOOD DISORDER SPECIFIERS Severity/Psychotic/Remission Mild Moderate Severe Without Psychotic features MDE (markedly interferes) Manic / Mixed (almost continual supervision required to prevent harm) Severe With Psychotic Features (delusions or hallucinations) Mood-Congruent Mood-Incongruent In Partial Remission (full criteria are not met) In Full Remission (no significant signs or symptoms for > 2 months) Chronicity Only for MDE > 2 years Applied to current MDE, Manic Episodes, or Mixed Episodes in MDD, Bipolar I or Bipolar II (MDE) Poor prognostic factors for mood disorder patients Long duration of episodes Temporal dissociation between the mood and the psychotic symptoms Poor pre-morbid history of social adjustment Mood-congruent psychoses Are associated with psychotic mood disorders Mood-incongruent psychoses Are associated with schizoaffective disorder or schizophrenia Psychotic features affect treatment Also require antipsychotic drugs May need ECT

MOOD DISORDER SPECIFIERS (cont.) : MOOD DISORDER SPECIFIERS (cont.) Melancholic features A. Either of the following Loss of pleasure in all, or almost all, activities Lack of reactivity to usually pleasurable stimuli B. > 3 of the following Distinct quality of depressed mood Diurnal variation (am worse) Early morning awakening by > 2 hrs Marked psychomotor retardation or agitation Significant anorexia or weight loss Excessive or inappropriate guilt Applied to current MDE in MDD, Bipolar I or Bipolar II Disorder Not uncommon to also have suicidal ideation More likely to occur in those with psychotic features Associated with change in autonomic nervous system and endocrine functions (dexameth non-supp, cortisol) Also referred to as “endogenous depression” or depression that arises in the absence of external life stressors or precipitants Psychomotor changes are almost always present Less likely to have A pre-morbid personality disorder A clear precipitant Response to a trial of placebo medication

MOOD DISORDER SPECIFIERS (cont.) : MOOD DISORDER SPECIFIERS (cont.) Atypical features A. Mood reactivity (mood brightens in response to + events) B. > 2 of the following Significant weight gain or increased in appetite Hypersomnia (> 10 hrs) Leaden paralysis (heavy, leaden feeling in arms & legs) Long-standing pattern of interpersonal rejection sensitivity (not limited to episodes of mood disturbance) C. Criteria are not met during the same episode for With melancholic features, or With catatonic features Applies for the most recent 2 wks of a current MDE or other depressive episode in MDD, Bipolar I or Bipolar II Disorder, and in Dysthymic Disorder 2-3 F > M Patients with atypical features are more likely to have A younger age at onset of depression Younger age at episode (older individuals may more often have melancholic features) More severe psychomotor slowing More frequent coexistent diagnoses Panic disorder High incidence and severity of anxiety symptoms Substance abuse or dependence Somatization disorder Long-term course (less episodic and with only partial interepisode recovery) Bipolar I D/O, Bipolar II D/O, and Recurrent MDD, occurring in a seasonal pattern More likely to respond to monoamine oxidase inhibitors (MAOIs) than to tricyclic antidepressants (TCAs); less clear w SSRIs???

MOOD DISORDER SPECIFIERS (cont.) : MOOD DISORDER SPECIFIERS (cont.) Catatonic features > 2 of the following Motoric immobility (catalepsy or stupor) Excessive motor activity (purposeless and not influenced by external stimuli) Extreme negativism (motiveless resistance to all instructions or attempts to move from rigid posture) or mutism Peculiarities of voluntary movement (posturing, stereotyped, prominent mannerisms, prominent grimacing) Echolalia or echopraxia Applied to current MDE, Manic Episodes, or Mixed Episodes in MDD, Bipolar I or Bipolar II (MDE) 25-50% occur in Mood Disorders (most commonly with Bipolar I Disorder) 10-15% occur in Schizophrenia, Catatonic Type Catatonic features can also be a consequence of Catatonic Disorder Due to General Medical Condition (infectious, metabolic, neurological) Medication-Induced Movement Disorder (including Neuroleptic Malignant Syndrome)

MOOD DISORDER SPECIFIERS (cont.) : MOOD DISORDER SPECIFIERS (cont.) Postpartum Onset Onset of episode within 4 weeks postpartum Postpartum-onset mood episodes present Without psychotic features, or With psychotic features 1/500 – 1/1,000 deliveries More common in Primiparous women Women with prior postpartum mood episodes 30-50% risk of recurrence with each subsequent delivery Prior Mood Disorder (especially Bipolar I Disorder) Family history of Bipolar Disorder Infanticide is most often associated with these episodes that are characterized by command hallucinations to kill the infant or delusions that the infant is possessed Applied to current or most recent MDE, Manic Episode, or Mixed Episode in MDD, Bipolar I or Bipolar II Disorder Also applied to Brief Psychotic Disorder Potential impact of breast-feeding on treatment planning (i.e. med choices) Long-term implications on subsequent family-planning

MOOD DISORDER SPECIFIERS DESCRIBING COURSE OF RECURRENT EPISODES : MOOD DISORDER SPECIFIERS DESCRIBING COURSE OF RECURRENT EPISODES With & Without full inter-episode recovery Seasonal pattern Rapid cycling

MOOD DISORDER SPECIFIERS DESCRIBING COURSE OF RECURRENT EPISODES : MOOD DISORDER SPECIFIERS DESCRIBING COURSE OF RECURRENT EPISODES Recurrent Major Depressive Disorder With Full Interepisode Recovery Without Full Inter-episode Recovery With No antecedent Dysthymic Disorder Best future prognosis Pattern persists More recurrences With antecedent Dysthymic Disorder Rare ( Only 3% of MDD cases) Pattern persists More recurrences Double Depression ( 20-25% of MDD cases) Applied to Recurrent MDE Bipolar I or II Disorder Longitudinal Course Specifiers

MOOD DISORDER SPECIFIERS DESCRIBING COURSE OF RECURRENT EPISODES (cont.) : MOOD DISORDER SPECIFIERS DESCRIBING COURSE OF RECURRENT EPISODES (cont.) Seasonal pattern Seasonal Affective Disorder = S.A.D. A. Regular temporal relationship between the onset of MDE and a particular time of the year (i.e. fall or winter) Not obvious seasonal-related psychosocial stressors (i.e. winter unemployment) B. Full remissions or a polarity switch also occurs at a characteristic time of the year (i.e. MDE disappears in the spring) C. In the last 2 years, 2 MDE demonstrate the seasonal relationships in criteria A & B, and no non-seasonal MDE have occurred during the same period D. Seasonal MDE substantially outnumber the non-seasonal MDE throughout the lifetime Applied to MDE pattern in Bipolar I or II Disorder MDD, Recurrent MDE-SAD is characterized by Prominent anergy Hypersomnia Overeating & weight gain Carbohydrate cravings Prevalence MDE < = > Bipolar Disorder ?? Bipolar II > Bipolar I Younger persons at higher risk for winter depressive episodes Mean age at presentation = 40 years Women = 60-90% of SAD cases Likely to respond to light-therapy

MOOD DISORDER SPECIFIERS DESCRIBING COURSE OF RECURRENT EPISODES (cont.) : MOOD DISORDER SPECIFIERS DESCRIBING COURSE OF RECURRENT EPISODES (cont.) Rapid Cycling > 4 episodes of a mood disturbance in the previous 12 months that Meet criteria for MDE, Manic, Mixed, or Hypomanic Episode Episodes are demarcated by > 2 months of partial or full remission Switch to an episode of opposite polarity Manic, Hypomanic & Mixed Episodes are counted as being on the same pole Exclude episodes directly caused by a substances or a general medical condition Applied to Bipolar I or II Disorder In 10-20% of Bipolar Disorder patients in Mood Disorder clinics No familial pattern of inheritance 70-90% are women Not linked to any phase of the menstrual cycle May be associated with Hypothyroidism Neurological conditions (MS) Mental Retardation Head injury Antidepressant treatment Can occur at any time during the course of Bipolar Disorder May appear and disappear, particularly if it is associated with antidepressant use Associated with poorer long-term prognosis

Mood Disorders : Mood Disorders Epidemiology

Epidemiology : Epidemiology MAJOR DEPRESSIVE DISORDER BIPOLAR DISORDER 15% Lifetime prevalence Type I: 1-1.6% Type II: 0.5% 2 F > 1 M (10 - 25% F vs. 5 - 12% M) Gender F = M 50% between 20-50 Childhood to 50 40 Age of onset: Range Mean Childhood to old age 30 Lesser than in Bipolar Disorder Genetic factors Greater than in MDD & Schizophrenia 2-3x Bipolar I Disorder dx 1.5-2.5x MDD dx 33-90% MZ >> 5-25% DZ First degree relatives (vs. relatives of control probands) Twin studies 8-10x Bipolar I Disorder dx 2-10x MDD dx 50% MZ > 10-25% DZ

Genetics Risk (%) of Developing the Condition in Relatives of Probands : Genetics Risk (%) of Developing the Condition in Relatives of Probands Relationship to Patient Approximate Risk for Schizophrenia Approximate Risk of Bipolar Disorder No relation (general population) 1 1 First Degree Relative (sibling, dizygotic twin or parent) 10 20 Child of Two Ill Parents 40 60 Monozygotic Twin 50 75

PowerPoint Presentation : Epidemiology DYSTHYMIC DISORDER CYCLOTHYMIC DISORDER 6% (with or without superimposed MDD) Lifetime prevalence 0.4% - 1% 15%-50% risk of developing Bipolar I or II Disorder F = M Gender 3 F > 2 M Early & insidious (childhood, adolescence, early adults) Most cases by 20 years of age Age of onset: Range Mean 50-75% between 15 & 25 Low spontaneous remissions (10%) Genetic factors - 1 0 relatives of Dysthimics: Dysthymic Disorder & MDD - 1 0 relatives of MDD: Dysthymic Disorder First degree relatives (vs. relatives of control probands) - 1 0 relatives of Cyclothymics : MDD & Bip I or II & Substance-related disorders - 1 0 relatives of Bip I Disorder: Cyclothymic Disorder

Depressive Disorders : Depressive Disorders Clinical Features

Major Depressive Disorder Clinical Features : Major Depressive Disorder Clinical Features Associated symptoms Tearfulness, irritability, obsessive ruminations, anxiety, panic attacks that may meet criteria of Panic Disorder, phobias, excessive worries over physical health, complaints of aches and pains, less satisfying or tolerance of social interactions, sexual dysfunction (anorgasmia ♀, erectile dysfunction ♂), alcohol or other substance abuse, marital (divorce)/ occupational (job loss)/academic (truancy, school failure) problems, difficulties finishing tasks, abnormal menses, cognitive symptoms (concentration) Depressed mood often has a distinctive quality Different from normal sadness or grief Sometimes described as agonizing emotional pain

Major Depressive Disorder Clinical Features (cont.) : Major Depressive Disorder Clinical Features (cont.) Suicide risk 66% contemplate it 10-15% commit suicide Those at highest risk Depressed individuals with psychotic features Those hospitalized with a suicide attempt or suicide ideation have a higher lifetime risk of successful suicide Family history of completed suicide Concurrent substance use Premature death from general medical conditions Some patients seem unaware of their depression and do not complain of a mood disturbance

Dysthymic Disorder Clinical Features : Dysthymic Disorder Clinical Features Presents with symptoms of lack of say in life and preoccupation with inadequacy Symptoms tend to outnumber signs More subjective than objective depression Psychomotor agitation or retardation is not observed Marked disturbances in appetite and libido are uncharacteristic (Often lifelong) chronic gloominess and fluctuating depressive picture that merges imperceptibly with the patient’s habitual self has raised debate whether it belongs in Axis I or Axis II Confluence of data on the efficacy of many classes of antidepressants Should not be denied the potential benefit of antidepressants

Major Depressive Episodes : Major Depressive Episodes Other Clinical Consequences & Clinical Outcomes

Depression-Related Cognitive Disorder : Depression-Related Cognitive Disorder Associated with chronicity, recurrence, and refractory illness Associated with increasing the risk of degenerative dementing disorders in old age Associated with late-onset illness May be the first sign of degenerative process 10-15% annual progression to dementia

Major Depressive Disorder : Major Depressive Disorder Psychosocial Etiology

Depressive Disorders: Psychosocial Etiology : Depressive Disorders: Psychosocial Etiology Psychoanalytical Freud’s structural theory Introjection of the lost object Is the most common defense mechanism in depression Superego, unable to retaliate against the lost object externally, directs the anger against the introject in the ego ( anger turned against the self ) Leads to depressive symptoms of lack of energy available to the ego Cognitive Low self-esteem and negative interpretation of events Learning Theory “Learned helplessness”, following futile attempts to escape bad situations Social Loss of a parent before adolescence (~ <12) Loss of a child or spouse in adulthood

Major Depressive Disorder : Major Depressive Disorder Pathophysiology

Pathophysiologic Findings in Major Depressive Disorder : Pathophysiologic Findings in Major Depressive Disorder Sleep neurophysiology Trait-like abnormalities persistent upon remission of index episode, associated with Diminished response to psychotherapy Preferential benefit from pharmacotherapy Greater risk of relapse or recurrence Present in 40% outpatient MDD & in 80% if inpatient MDD Reduced slow wave sleep (deep sleep stages 3 & 4) Causes blunted secretion of GH after sleep Increased nocturnal arousal Increased awakenings Reduced total sleep time (TST) Increased REM sleep Increased core body temperature Shortened REM latency Brain imaging L > R frontal hypometabolism (reversed finding seen in mania)

Pathophysiologic Implications of Chronic or Recurrent MDD : Pathophysiologic Implications of Chronic or Recurrent MDD Neuroendocrine Limbic-HPA axis hyperactivity Increased CSF CRH Hypercortisolism Failed dexamethasone suppression of cortisol Molecular Neurotrophic and atrophic factors Neuroanatomical Reduced neuronal plasticity Reduced hippocampal neurogenesis Immunological Impaired cellular immunity Neurophysiological Increased amygdala glucose metabolism Reduced anterior cerebral blood flow Neurocircuitry Medial PFC – Thalamo – Striatal – Cortical hyperactivity Atrophy of the human hippocampus Disorder References Cushing's syndrome Starkman et al 1992 Recurrent depressive illness Sheline et al 1996 Posttraumatic stress disorder Gurvits et al 1996, Bremner et al 1995 Schizophrenia Fukuzako et al 1996, Bogerts et al 1993 Aging, preceding dementia Convit et al 1995, Golomb et al 1994 Dementia de Leon et al 1993

MOOD DISORDERS OVERVIEW : MOOD DISORDERS OVERVIEW Stressful life events Recent stressful events are the most powerful predictors of the onset of a depressive episode Individual susceptibility related to idiosyncratic meaning attached to the event Life event most often associated with development of depression is loosing a parent before age 11 The environmental factor most often associated with the onset of an episode of depression is the loss of a spouse Stressful life events more often precede first, rather than subsequent episodes of mood disorders (kindling hypothesis) Personality predisposition No single personality trait or type uniquely predisposes a person to depression Although, OCPD & Cluster B may be at greater risk than Cluster A No particular personality disorder is associated with latter development of bipolar I disorder Dysthymic Disorder and Cyclothymic Disorder patients are at greater risk of later major depression or bipolar I disorder Genetics Genes so far identified may influence inheritance of mood disorders of specific studied families but not others

Symptoms – Neuroanatomical Correlations : Symptoms – Neuroanatomical Correlations Limbic system (including amygdala) Emotions Anxiety Sympathetic tone Hypothalamus Endocrine changes Immunological changes Chronobiological changes Basal ganglia Psychomotor changes Motivation Cognitive Hippocampus Cognitive

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PowerPoint Presentation : From:Neurobiología de la depresión Zandio M, et al. M. Anales . 2002;25(3):43-62

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Reduction in Hippocampal Complex Volume in Major Depression: MRS : From: Campbell, S and Macqueen G. J Psychiatry Neurosci . 2004;29(6):417-426 Reduction in Hippocampal Complex Volume in Major Depression: MRS

HIPPOCAMPAL NEUROGENESIS Control Rat vs. Stressed Rat : HIPPOCAMPAL NEUROGENESIS Control Rat vs. Stressed Rat Arrows point at stained new nuclei. When stressed in a restrained environment, neurogenesis is reduced (right picture).

PowerPoint Presentation : Requirement of Hippocampal Neurogenesis for the Behavioral Effects of Antidepressants Santarelli L, et al. Science . 2003;301(5634):805-9 Green = “stem cells” Blue = new neurons

Requirement of Hippocampal Neurogenesis for the Behavioral Effects of Antidepressants Santarelli L, et al. Science. 2003;301(5634):805-9 : Experiment Behavior Hippocampal Neurogenesis Stress Alone Depressed Decreased Stress Plus Prozac Normal Normal Stress + x-ray + Prozac Depressed (decreased by the x-rays) Requirement of Hippocampal Neurogenesis for the Behavioral Effects of Antidepressants Santarelli L, et al. Science . 2003;301(5634):805-9 Here then is the key result: without neurogenesis in the hippocampus, there was no protective effect from the antidepressant. The implication is that antidepressants work by promoting neurogenesis.  When that mechanism in the brain was blocked (in this case by x-ray treatment, before the animal went through the stress), the antidepressant--which had been very effective in other mice not receiving x-rays -- was not effective.

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PowerPoint Presentation : The Limbic-Hypothalamic-Pituitary-Adrenal Axis in Depression Hyperactivity of the LHPA axis is a well documented phenomena in MDD. This dysregulation is manifested, among other things, by cortisol hypersecretion , failure to suppress cortisol secretion after dexamethasone administration , exaggerated adrenal responses to endocrine challenges, and blunted ACTH response to CRH administration (Carroll et al., 1976; Kalin et al., 1987; López et al., 1987; Gold et al., 1988; Kathol et al., 1989b). This last observation has been interpreted as evidence of pituitary downregulation of CRH receptors secondary to an increase in secretion of CRH. There is indeed good evidence of increased central drive, based on increased activity at the nadir of the circadian rhythm (Young et al., 1995) as well as more direct findings of elevated CRH in the CSF of depressed patients (Nemeroff et al., 1984), and increased CRH immunoreactivity and mRNA levels in the PVN (Raadsheer et al., 1994, 1995). Interestingly, post-mortem studies have also found evidence of chronic LHPA activation in suicide victims, such as adrenal hyperplasia (Dorovini-Zis and Zis, 1987), downregulation of CRH receptors (Nemeroff et al., 1988), and increases in proopiomelanocortin mRNA, the precursor for ACTH, in the pituitary (López et al., 1992). It is not known whether these LHPA changes in suicide are due to the fact that a significant subset of suicide victims are patients with depressive disorders, to the stress surrounding the suicide itself, or to a neurobiological "abnormality" common to all suicides irrespective of diagnosis. We have found, in a group of suicide victims with a history of depression, decreases in hippocampal MR mRNA levels (López et al., 1998), and more recently, a decrease in GR mRNA levels in prefrontal cortex (unpublished observation) an area of the brain which is associated with higher cognitive, and executive function. We don�t know whether these changes represent a genetic, or developmental, vulnerability "marker" for suicide, or for depression. Nevertheless, these findings are consistent with a history of exposure to chronic stress and/or to high peripheral glucocorticoid levels (Herman and Watson, 1994; Herman et al., 1995). Historically, the presence of LHPA overactivity in patients with depression was believed by many to be a "secondary" phenomena of the illness, reflecting either a central monoaminergic disturbance, the stress of the illness, or both. However, over the past few years, it has become clearer that the LHPA abnormalities in MDD are intimately linked to the pathohysiology of the disease. This change in perspective was stimulated in part by the increased awareness that glucocorticoids, the final products of the LHPA axis have been shown to have profound effects on mood and behavior (McEwen 1987). For example, a high incidence of depression is linked to pathologies involving elevated corticosteroid levels, such as Cushing's syndrome. This corticosteroid-induced depression usually disappears when corticosteroid levels return to normal (Kathol 1985; Murphy 1991). In fact, it has become increasingly clear, from both animal and clinical studies, that circulating glucocorticoid levels provide important hormonal control of affect, which may be mediated by steroid-induced modulation of central limbic circuitry (McEwen 1987). The precise mechanism by which corticosteroids exert this influence on affect is not well understood. However, this mechanism is likely to involve interactions with brain neurotransmitters, since we know that central control of affect is intimately associated with the actions of the monoamines serotonin, norepinephrine and dopamine.

PowerPoint Presentation : Serotonin Receptors and Depression The serotonin system has been widely investigated as a key element in the pathophysiology of Depression (Meltzer, 1989), and of suicide (Mann et al., 1989), and as a mediator of the therapeutic action of antidepressants (Berendsen, 1995). Although the 5-HT system has many components, the three 5-HT molecules believed to be most closely associated with the neurobiology of mood are the serotonin transporter (5-HTt), the serotonin 1a receptor (5-HT1a), and the serotonin 2a receptor (5-HT2a, formerly 5-HT2). Most new (as well as older) antidepressants inhibit the re-uptake of serotonin from the synapse, and alter 5-HTt protein and mRNA levels (López et al., 1994; Owens and Nemeroff, 1998). Animal studies have also demonstrated that chronic antidepressant administration affects the function and number of the 5-HT1a and 2a receptors. Many electrophysiological studies have shown that antidepressants "upregulate" or "sensitize" 5-HT1a function in the hippocampus, while at the same time they "down-regulate" or "desensitize" 5-HT1a function in the raphe, where it acts as an inhibitory somatodendritic receptor (Blier and de Montigny, 1994). Some studies have also reported a modest increase in 5-HT1a receptor number in hippocampus following antidepressant administration to rodents (Welner et al., 1989; Klimek et al., 1994). We have found that suicide victims with a history of depression have decreases in 5-HT1a gene expression in hippocampus (López et al., 1998). These changes are in the opposite direction of what is observed with antidepressant treatment in rat hippocampus. The 5-HT2a receptor has also been shown to be affected by chronic antidepressant treatment. Most, but not all, studies have reported decreases in 5-HT2a binding in the prefrontal cortex after chronic antidepressant administration (Peroutka and Snyder, 1980; Bourin and Baker, 1996). The opposite changes (5-HT2a upregulation) are found in the prefrontal cortex of suicide victims (Mann et al., 1986; Arango et al., 1990; Hrdina et al., 1993), although these findings are not universal (Stockmeier, 1997). In addition, subjects with a history of MDD dying of natural causes have increases in 5-HT2a binding in the prefrontal cortex (Yates et al., 1990). These findings have led several investigators to propose that postsynaptic 5-HT1a and 5-HT2a receptors have functionally opposing effects (Schreiber and De Vry, 1993), that a disturbed balance of these receptors may be contributing to the pathophysiology of Depression (Berendsen, 1995), and that restoring this balance is necessary for antidepressant action (Borsini, 1994).

PowerPoint Presentation : Interaction Between the LHPA axis and Serotonin Another level of complexity is added by the fact that 5-HT and the LHPA axis interact at multiple levels. For example, it is known that some of the 5-HT neurons arising from the nucleus raphe dorsalis and nucleus raphe magnus project to the PVN and synapse onto CRH neurons (Fuller, 1992). 5-HT neurons also project to other brain areas, such as the amygdala and the suprachiasmatic nucleus, which are thought to modulate the function of the PVN (Törk, 1990). Pharmacological stimulation with 5-HT agents can activate ACTH and cortisol release (Fuller, 1992). Many brain areas that express 5-HT receptors also have abundant concentrations of corticosteroid receptors. In the limbic system in particular, the hippocampus has high concentrations of 5-HT1a in the same neurons that contain abundant GR and MR receptor levels, and the prefrontal cortex is rich in 5-HT2a receptors (Pazos and Palacios, 1987), as well as GR receptors. Interestingly, unlike rodents, human prefrontal cortex also has significant amounts of MR mRNA. This constitutes anatomical evidence suggesting that MR may have a more expanded role in modulating brain function in humans than in rodents. Furthermore, the co-localization of MR and GR in prefrontal cortex suggest that both of these receptors are capable of modulating higher brain functions, such as mood, social behavior, and cognitive processing, perhaps by interacting with 5-HT receptors. Serotonin and corticosteroid receptors not only interact anatomically, but also functionally. It has been reported that administration of serotonin can up-regulate GR in the hippocampus, and that conversely, pharmacological destruction of serotonergic projections decreases GR and MR mRNA levels in the hippocampus (Betitto et al., 1990; Seckl et al., 1990). Regulation in the other direction, i.e. glucocorticoid regulation of 5-HT receptors, has also been reported. Animal studies have demonstrated that adrenalectomy and corticosteroid administration powerfully regulate 5-HT1a receptor number and mRNA in the hippocampus (Chalmers et al., 1992, 1994; Kuroda et al., 1994). This effect of glucocorticoids seems to be specific for the postsynaptic 5-HT1a receptor, since the somatodendritic 5-HT1a is not affected by these manipulations (Chalmers et al., 1992). The 5-HT2a receptor is also sensitive to changes in peripheral glucocorticoid levels. Upregulation of 5-HT2a in rat neocortex cortex has been reported following ten days of exogenous administration of ACTH (Kuroda et al., 1992). This effect is abolished by adrenalectomy and mimicked by corticosterone administration for ten days. Dexamethasone treatment for the same amount of time also causes a dose dependent increase in 5-HT2a binding in cortex (Kuroda et al., 1993), suggesting that this effect is mediated by GR, since dexamethasone is a potent GR agonist. Interestingly, the effect of corticosteroids on 5-HT2a receptor number seems to be specific for the cortex. Dexamethasone did not alter 5-HT2a binding in rat hippocampus. Given the relatively equal abundance of MR and GR in the hippocampus, and the preponderance of GR in rat frontal cortex, it is plausible that 5-HT receptor regulation in the cortex is mediated through different mechanisms than in the hippocampus.

PowerPoint Presentation : Stress, Serotonin and the LHPA axis In reviewing the clinical, psychological and biological literature on depressive illness, one factor that emerges as being closely associated with depression is stress. Stress and depression have been linked in a variety of ways: For example, both physical and psychological stressors have been shown to be temporally (and perhaps causally) related to the onset of depressive episodes (Post 1992). Some studies have suggested that, at least for recurrent depression, stressful life events are more common in "non-endogenous depression" (Frank et al., 1994). Other studies have found that stressful life events are significantly correlated even with the first episode of psychotic/endogenous depression (Brown et al., 1994). This is not to say that stress "causes" depression in people. Rather, stress is very likely interacting with an endogenous genetic predisposition, such that in some vulnerable individuals, a stressor can precipitate a mood disorder (i.e. vulnerability + stress = depression). In fact, studies in twins by Kendler et al have demonstrated a clear interaction between genetic substrate and a recent stressful life event in the precipitation of a depressive episode: the more the genetic "loading" for depression, the more likely than a stressful event will trigger an episode. There are of course cases in which the genetic "loading" or predisposition is so high, that an episode of depression can occur in the absence of any apparent precipitating factors. Another important link between depression and stress is the fact that both the LHPA and 5-HT systems, in addition to been involved in the pathophysiology of depression, are also, as we have discussed above, critical contributors to the neurobiology of stress (McEwen 1987) . Therefore, studying the neurobiology of stress by focusing on these two systems has given us important clues into the pathophysiology of affective illness, shed light on the actions of antidepressants, and begin to reveal how stress and mood disorders are related. We have used chronic unpredictable stress, a postulated animal model of depression (Katz and Sibell, 1982; Armario et al., 1988) to investigate the parallel changes in 5-HT and LHPA related molecules, and to study how chronic stress and circulating glucocorticoids influence the 5-HT receptor system (López et al., 1997, 1998,1999b). In this paradigm, rats are exposed to different mild to moderate stressors everyday, therefore making the stress "unpredictable" from day to day. Rats that undergo this treatment show LHPA overactivity, and increases in peripheral glucocorticoids, very similar to those found in MDD (Chapel et al., 1996; Armario et al., 1988). We found that rats subjected to this paradigm show a significant decrease in 5-HT1a mRNA and binding in the hippocampus, as well as decreases in MR mRNA levels in this same region (López et al., 1998). Chronic unpredictable stress also causes a significant increase in 5-HT2a receptor and mRNA levels in the prefrontal cortex (López et al, submitted). As stated above, these "opposite" effects (hippocampal 5-HT1a downregulation, cortical 5-HT2a upregulation) are also found in suicide victims with a history of depression (Mann et al., 1989; López et al., 1997). It is not clear if these 5-HT receptor changes are due to a direct effect of corticosteroids on the receptor themselves, or if they are secondary to corticosteroid induced changes in serotonin synthesis and turnover. However, the effects of chronic stress on these 5-HT receptors are prevented if the stress-related glucocorticoid increase is abolished. No changes are found in the presynaptic 5-HT transporter sites after chronic stress, suggesting that the effects are mainly in the postsynaptic receptors (López et al., 1997, 1998).

PowerPoint Presentation : Antidepressant Medications, the LHPA Axis and 5-HT Receptors The LHPA overactivity observed with chronic unpredictable stress can also be prevented by the chronic administration of either imipramine or desipramine, two tricyclic antidepressants (López et al., 1998). Both desipramine and imipramine also reverse the stress induced downregulation of 5-HT1a in hippocampus, and the 5-HT2a upregulation in cortex. On the other hand, zimelidine and fluoxetine, two specific serotonin reuptake inhibitors, are unable to prevent the stress-induced elevation in corticosterone levels. This failure to prevent the LHPA overactivity is associated with a failure to restore the 5-HT receptor changes to baseline levels. This suggests that failure of an antidepressant to reverse the LHPA hypersecretion is associated with a failure to prevent the 5-HT receptor "dysregulation" secondary to chronic stress. We have proposed that this may be one of the neurobiological mechanisms underlying "treatment resistance" in patients with severe depression (López et al., 1997). There is some clinical evidence that these mechanisms may be operating in depressive disorders. Persistence of hypercortisolemia after antidepressant administration in depressed patients has been associated with relapse and poorer treatment outcome (Greden et al., 1983; Ribeiro et al., 1995). In addition, some clinical studies have found that tricyclics are more effective than SSRIs in the treatment of melancholia (Danish University Antidepressant Group, 1986, 1990; Roose et al., 1994), Venlafaxine, an antidepressant with both norepinephrine and 5-HT reuptake activity, was reported to be more effective than fluoxetine in treating melancholic depression (Clerc et al., 1994), and in comorbid depression and anxiety (Silverstone et al., 1999). Since melancholia and severity of depression are associated with a higher incidence of hypercortisolemia (Kathol et al., 1989; Meador-Woodruff et al., 1990), it is possible that the presence of a severely disturbed LHPA axis in this population may be contributing to the relative resistance to SSRI treatment. Interestingly, many augmentation strategies in treatment resistant patients are in effect attempts to broaden the biochemical profile of the pharmacological treatment, which may be more effective in reversing LHPA overactivity than a treatment whose main impact is in a single neurotransmitter system. Interplay Between Stress, the LHPA Axis, Serotonin, and Antidepressants Based on the animal and human studies reviewed here, we can generate a working model of the interplay between stress, the LHPA axis, 5-HT receptors, and their potential interactions in suicide and depression. Figure 2 illustrates this model (solid arrows represent known effects, dashed arrows represent possible effects). While it is possible that some monoamine receptor changes are due to antecedent changes in their endogenous ligands, we propose that many of the receptor changes observed may be a result of the LHPA overactivity present in at least some suicide victims, in particular those with a history of affective disorders. The rationale for this hypothesis derives from the above evidence, which can be summarized as follows: 1) Depressed patients, as well as suicide victims, show evidence of overactivity of the LHPA axis. 2) Chronic stress and/or high steroid levels in rats result in an alteration of specific 5-HT receptors (e.g. increases in cortical 5-HT2a, decreases in hippocampal 5-HT1a). 3) Many human studies show the same receptor changes in the brain of suicide victims (increases in cortical 5-HT2a, decreases in hippocampal 5-HT1a) as found in hypercorticoid states. 4) Chronic antidepressant administration causes opposite 5-HT receptor changes to those seen with chronic stress 5) Antidepressant administration reverses the overactivity of the LHPA axis. If indeed the 5-HT1a and 5-HT2a receptors have at least a partial role in controlling affective states (either directly or secondarily through other systems), then their modulation by corticosteroids provides a potential mechanism by which these hormones may regulate mood. This of course does not exclude the possibility that stress can be simultaneously acting through other systems, such as the CRH receptors, thereby synergistically affecting mood and behavior. Antidepressants can counteract this phenomenon by affecting 5-HT receptor function directly and by simultaneously regulating stress induced corticosteroid secretion.

PowerPoint Presentation : Conclusion Corticosteroid modulation of 5-HT receptors has important implications for the pathophysiology and treatment of mood disorders, and perhaps suicide. This may be one of the mechanisms by which stressful events can precipitate depressive episodes in some (genetically) vulnerable individuals and or precipitate suicidal behavior. Another implication is that altered 5-HT levels or metabolism do not necessarily have to be present for 5-HT receptor abnormalities to occur. Based on the animal data, it is apparent that specific 5-HT receptors may be directly regulated in response to alterations of corticosteroid levels. Thus, in depressed patients normal levels of serotonin and its metabolites may not necessarily reflect normal central 5-HT activity. An important therapeutic implication of this model is the prediction that agents that can reduce the stress response, and/or decrease LHPA activation, will be useful in the pharmacological treatment of anxiety, depression and perhaps suicidal behavior. In fact, patients with MDD who are resistant to antidepressant treatment, have been reported to improve after receiving steroid suppression agents, like ketoconazole (Murphy et al 1991; Wolkowitz et al 1993). However, these agents have many side effects, and are often difficult for patients to tolerate. In this respect, CRH receptor antagonists, which are currently under development, may provide us with a new therapeutic weapon to treat these patients (De Souza 1995, Chalmers et al., 1996). These compounds could be used in conjunction with antidepressants, as adjuvants or augmenting agents, and may decrease treatment resistance. This agents may also be useful in monotherapy, since preventing hypercortisolemia may be translated into an improvement of monoaminergic receptor function. The use of modern biochemical and pharmacological tools, coupled with our increased understanding of the neurobiology of depression, should allow us to test these hypotheses, first in animal models and then directly in patients with affective illness.

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PowerPoint Presentation : CORTISOL Hippcopampus & Raphe Nucleus End-organ effects

Trophic-Atrophic Balance : From: www.psycheducation.org By: Jim Phelps, MD Nucleus Mitochodrion Trophic-Atrophic Balance CORTISOL GR BAG- 1 NE PKA CREB BDNF MAP/ERK 5-HT PI-3-K Lithium Valproate BCL-2 Glucose transporter GLUTAMATE NMDA receptor Ca 2+ PTP ROS BAD Akt GSK-3ß Trk B cAMP

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Depression Traced to Overactive Brain Circuit AC/medial PFC – Thalamo – Striato – Cortical Circuit : Areas that show over-activity following tryptophan depletion in depression patients in remission — and thought to reflect a trait dysfunction — include emotion regulating circuitry involving the anterior cingulate, thalamus, ventral striatum and orbitofrontal cortex. Source: NIMH Mood and Anxiety Disorders Program 2004 Depression Traced to Overactive Brain Circuit AC/medial PFC – Thalamo – Striato – Cortical Circuit

PowerPoint Presentation : Depression Traced to Overactive Brain Circuit A brain imaging study by the NIH's National Institute of Mental Health (NIMH) has found that an emotion-regulating brain circuit is overactive in people prone to depression — even when they are not depressed. Researchers discovered the abnormality in brains of those whose depressions relapsed when a key brain chemical messenger was experimentally reduced. Even when in remission, most subjects with a history of mood disorder experienced a temporary recurrence of symptoms when their brains were experimentally sapped of tryptophan, the chemical precursor of serotonin, the neurotransmitter that is boosted by antidepressants. Neither a placebo procedure in patients nor tryptophan depletion in healthy volunteers triggered the mood and brain activity changes. Brain scans revealed that a key emotion-processing circuit was overactive only in patients in remission — whether or not they had re-experienced symptoms — and not in controls. Since the abnormal activity did not reflect mood state, the finding suggests that tryptophan depletion unmasks an inborn trait associated with depression. Alexander Neumeister, M.D., Dennis Charney, M.D., Wayne Drevets, M.D., NIMH Mood and Anxiety Disorders Program, and colleagues, report on their positron emission tomography (PET) scan study in the August 2004 Archives of General Psychiatry. The NIMH researchers and others had previously shown that omitting tryptophan from a cocktail of several other essential amino acids washes out the precursor chemical from the blood and brain, depleting serotonin and often triggering symptoms in people with a history of depression — and even in healthy people from depression-prone families. This added to evidence that a genetic predisposition that renders some people vulnerable to inadequate serotonin activity may be at the root of the mood disorder. The researchers scanned subjects after their blood tryptophan levels were reduced by about three-fourths, using a radioactive tracer (a form of glucose, the brain's fuel), which reveals where the brain is active during a particular experimental condition. They randomly gave 27 unmedicated depressed patients-in-remission and 19 controls either pills containing seven essential amino acids, such as lysine and valine, or identical-looking placebo pills. Subjects received either the active pills or placebos in repeated trials over several days in a blind, crossover design. Sixteen (59 percent) of the patients experienced a transient return of symptoms under tryptophan depletion; their mood lifted to normal by the next day. Compared to controls, the patients showed increased brain activity in a circuit coursing through the front and center of the brain (orbitofrontal cortex, thalamus, anterior cingulate, and ventral striatum) — areas involved in regulating emotions and motivation that have been implicated in previous studies of depression. Whereas previous studies interpreted the circuit activation as a transient, mood-dependent phenomenon, the new evidence suggests that circuit over-activation is likely an underlying vulnerability trait, say the researchers. Because of its ability to unmask what appears to be a trait marker for major depressive disorder, the researchers suggest that tryptophan depletion may be a useful tool for studying the genetic basis of depression. "Since brain function appears to be disregulated even when patients are in remission, they need to continue long-term treatment beyond the symptomatic phase of their illness," noted Neumeister, who recently moved to the Yale University psychiatry department. Also participating in the research were: Drs. Allison Nugent, Tracy Waldeck, Omer Bonne, Earl Bain and Marilla Geraci, David Luckenbaugh, NIMH; Dr. Markus Schwarz, Munich University Hospital of Psychiatry, Dr. Peter Herscovitch, NIH Clinical Center PET Department.

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MDD Differential Diagnosis : MDD Differential Diagnosis Adjustment Disorder Uncomplicated Bereavement Bipolar I or II Disorder Generalized Anxiety Disorder Post-traumatic Stress Disorder Schizoaffective Disorder Duet to a General Medical Condition Pancreatic Cancer, CVA, Dementing illnesses, CNS tumors, Parkinson’s Disease, Huntington’s Disease, Hypo/Hyperthyroidism, Cushing’s Disease, Sleep Apnea Alcohol or Substance-Related Disorder

Major Depressive Disorder: Treatment : Major Depressive Disorder: Treatment

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PowerPoint Presentation : 2000 APA Guidelines for the Treatment of Major Depressive Disorder

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Brain Effects of Cognitive Behavioral Therapy and Anti-depressant Drugs : Brain Effects of Cognitive Behavioral Therapy and Anti-depressant Drugs

Electroconvulsive Therapy (ECT) : Electroconvulsive Therapy (ECT)

Phototherapy (Light Therapy) : Phototherapy (Light Therapy) One should be directly in front of the unit as the light shines into the users eyes. The eyes need be open , and sunglasses should not be worn. Instructed not to look directly at the light source, although there is no evidence of danger to the eyes. The light source should probably be placed above eye level “… the inferior retina contributes more to the light-induced suppression of melatonin than the superior retina at the photon dosages tested in this study. Findings suggest a greater sensitivity or denser distribution of photoreceptors in the inferior retina are involved in light detection for the retinohypothalamic tract of humans.” (Glickman G, et al. J Biol Rhythms. 2003 Feb;18(1):71-9) The most common device used for bright light therapy is a fluorescent light box which produces a light intensity of 2,500 to 10,000 lux at a comfortable distance (1-2') The light box intensity of 10,000 lux is much brighter than normal indoor light which is usually 300-500 lux, but not as bright as summer sunlight which can be as bright as 100,000 lux. Full-spectrum light is not necessary since intensity is most important, but a balanced-spectrum light minus UV-B emissions is considered ideal. Fewer headaches and eyestrain are associated with using balanced spectrum light. Other major indications are sleep disorders associated with Work shift (causing irritability) Jet lag Geriatric sleep disorders Known cause to switch to mania or hypomania on rare occasions (~1%) ? √

Light Therapy vs. Pharmacotherapy for SAD : Light Therapy vs. Pharmacotherapy for SAD As effective as fluoxetine in this comparative study Faster action at week one for some patients Lesser side effects Lam RW, et al. Evid Based Ment Health. 2007 Feb;10(1):26

Vagal Nerve Stimulation : Vagal Nerve Stimulation Studies designed for treatment of epilepsy found improvement in mood Similar to a cardiac pacemaker, but attached to the vagus nerve Preliminary studies have shown remission in chronic, recurrent major depressive disorder

PowerPoint Presentation : Vagal Nerve (Deep Brain) Stimulation

Transcranial Magnetic Stimulation : Transcranial Magnetic Stimulation

BIPOLAR DISORDERS : BIPOLAR DISORDERS

BIPOLAR DISORDER : BIPOLAR DISORDER

Evolving Spectrum Phenotypes : Increasing Severity Percent of Individuals BP I, II, and Spectrum BP II, I BP I Early onset, Severe BP I 4.0 2.0 1.5 1.0 7.8 Evolving Spectrum Phenotypes More severe episodes More chronic with a predominantly depressive course Most chronic with subsyndromal mixed and unstable courses Judd LL. 2003 ?

Bipolar Spectrum Disorders : Angst, 1998. Lewinsohn, 1995. Szadockzky, 1998. Bipolar Spectrum Disorders Bipolar I Bipolar II: depression plus hypomania Cyclothymia (Bipolar III) Hypomania, mood instability with antidepressants (Bipolar IV) Depressions with hyperthymia, early age onset, positive family history of bipolar disorder Subthreshold hypomania Depressed Mixed States Borderline Syndrome with Affective Lability Most controversial. Supported by Akiskal, Angst, MacKinnon & Pies Bipolar Spectrum

Screening Tool: Mood Disorder Questionnaire : Screening Tool: Mood Disorder Questionnaire Hirschfeld RM, et al. Am J Psychiatry . 2000;157:1873-1875.

Positive Mood Disorder Questionnaire for Bipolar Disorder in the Community : Positive Mood Disorder Questionnaire for Bipolar Disorder in the Community Diagnosed with bipolar disorder Diagnosed with depression but not bipolar disorder Neither bipolar disorder nor depression diagnosis 31% 49% N = 2,134 subjects who screened positive for bipolar disorder 80% of patients who screened positive for bipolar disorder had not been diagnosed with bipolar disorder Hirschfeld RM, et al. J Clin Psychiatry . 2003;64:53-59. 20%

Underrecognition of Bipolar Disorder Patients Treated for Depression in a Family Medicine Clinic : Underrecognition of Bipolar Disorder Patients Treated for Depression in a Family Medicine Clinic 649 outpatients receiving treatment for depression Screened positive* for BD – 21% Hirschfeld RM, et al. J Am Board Fam Pract . 2005;18:233-239. Estimated bipolar prevalence among 649 depressed patients ~ 28% MDQ sensitivity = 58%; MDQ specificity = 93%; based on Structured Clinical Interview for DSM-IV (SCID) *Using the Mood Disorder Questionnaire (MDQ) BD = bipolar disorder

Differential Diagnosis: MDD or Bipolar Disorder? : Differential Diagnosis: MDD or Bipolar Disorder? 4. Mania Symptoms: Distractibility Decreased need for sleep Grandiosity / Flight of ideas / Racing thoughts Irritability / Risky behavior / Pressured speech 2. Course of Illness: Illness onset < 25 years Increased overall episodes Postpartum onset Highly recurrent depression 3. Treatment Response: Multiple treatment failures Nonresponse or erratic response to antidepressants Suboptimal outcome with antidepressant Family History: Higher rates of psychiatric illness Positive for bipolar disorder 5. Associated Features: Unevenness in intimate relationships Frequent career changes High prevalence of comorbidities (eg, substance use disorders) Key Elements Primary care practitioners are uniquely positioned to recognize Bipolar Disorder

Limitations of DSM-IV Criteria : Limitations of DSM-IV Criteria 4-day duration requirement for hypomania exceeds the typical clinical span of 1-3 days Modal Duration of Hypomania is 2 Days Akiskal, et al. ( Am J Psychiatry , 1977) Akiskal, et al. ( Arch Gen Psychiatry , 1979) Wicki and Angst. ( Eur Arch Psychiatr Clin Neuro , 1991) Cassano, et al. ( J Affect Disord , 1992) Manning, et al. ( Compr Psychiatry , 1997) Angst. ( J Affect Disord , 1998)

Limitations of DSM-IV Criteria : Limitations of DSM-IV Criteria 4-day duration requirement for hypomania exceeds the typical clinical span of 1-3 days Mixed episodes often do not meet full criteria for both depression and mania McElroy,S DSM-IV Mixed Mixed State Variations Akiskal HS. J Clin Psychopharmacol. 1996

Limitations of DSM-IV Criteria : Limitations of DSM-IV Criteria 4-day duration requirement for hypomania exceeds the typical clinical span of 1-3 days Mixed episodes often do not meet full criteria for both depression and mania Consideration required Major Depression dominated by hyperthymia Depressed-Mixed States Few manic symptoms (racing thoughts, sexual arousal) Akiskal HS, et al. J Affect Disord. 2000 Akiskal HS. J Clin Psychopharmacol. 1996

Bipolar Spectrum Disorders : Angst, 1998. Lewinsohn, 1995. Szadockzky, 1998. Bipolar Spectrum Disorders Bipolar I Bipolar II: depression plus hypomania Cyclothymia (Bipolar III) Hypomania, mood instability with antidepressants (Bipolar IV) Depressions with hyperthymia, early age onset, positive family history of bipolar disorder Subthreshold hypomania Depressed Mixed States Borderline Syndrome with Affective Lability Most controversial. Supported by Akiskal, Angst, MacKinnon & Pies Bipolar Spectrum

Bipolar Spectrum Along an Axis of Increased Frequency of Episodes : Bipolar Spectrum Along an Axis of Increased Frequency of Episodes

Krapelin’s Model of Mixed States (Chaotic Model) : Krapelin’s Model of Mixed States (Chaotic Model) Low intellect = sluggish thoughts or mere unproductive ruminations

Extrapolation of Krapelin’s Model to Explain Rapid Cycling : Extrapolation of Krapelin’s Model to Explain Rapid Cycling

Bipolar Disorder: Untreated vs. Treated Standardized Mortality Ratios : Bipolar Disorder: Untreated vs. Treated Standardized Mortality Ratios Cerebrovascular Cardiovascular Suicide Other Neoplasm Accidents All Causes Angst F. J Affct Disord. 2002;68(2-3):1670181 Standard Morality Ratio * * * * * *

FDA-approved Bipolar Disorder Treatments : FDA-approved Bipolar Disorder Treatments This chart does not imply comparable efficacy or safety profiles. All brand names and product names used in this slide are trade names, service marks, trademarks, or registered trademarks of their respective owners. Agents Manic Mixed Maintenance Depression ATYPICALS Aripiprazole (Abilify  ) + + + – Olanzapine (Zyprexa  ) + + + – Quetiapine (SEROQUEL  ) + – – + Risperidone (Risperdal  ) + + – – Ziprasidone (Geodon  ) + + – – OTHER Carbamazepine ER (Equetro TM ) + + – – Divalproex DR (Depakote  ) + – – – Divalproex ER (Depakote  ER) + + – – Lamotrigine (Lamictal  ) – – + – Lithium (Lithobid  , Eskalith  ) + – + – Olanzapine/fluoxetine (Symbyax  ) – – – + As of 11/06

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