Affective Spectrum Disorders

From 2009 Update in Psychiatry: Common Challenges in Psychopharmacology, presented by the Medical University of South Carolina Institute of Psychiatry

Educational Objectives

The goal of this program is to improve the diagnosis and treatment of affective spectrum disorders. After hearing and assimilating this program, the clinician will be better able to:

1.   Discuss the current debate surrounding pediatricbipolar disorder.

2.   Describe how the clinical presentation of bipolar disorder in youth differs from that in adults.

3.   Relate recently released practice parameters for pediatric bipolar disorder.

4.   Explain the relationship between anxiety and stress and certain medical disorders.

5.   Cite the mechanisms by which treatment for anxiety and depression result in improvement in medical disor­ders.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the plan­ning committee to disclose relevant financial relationships within the past 12 months that might create any personal con­flicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the speaker and the planning committee re­ported nothing to disclose. Dr. Koval presented information related to the off-label use of medications.

Acknowledgements

Drs. Koval and Lydiard were recorded at 2009 Update in Psychiatry: Common Challenges in Psychopharmacology, held May 29-30, 2009, in Charleston, SC, and sponsored by the Medical University of South Carolina Institute of Psychiatry. The Audio-Digest Foundation thanks the speakers and the Medical University of South Carolina Institute of Psychiatry for their cooperation in the production of this program.

Early-onset Bipolar Affective Disorder

Matthew S. Koval, MD, Associate Professor, Department of Psychiatry and Behavioral Sciences, Youth Psychiatry Divi­sion, Medical University of South Carolina, Charleston

What constitutes adolescent bipolar affective disorder (BPAD)? no debate if young person meets Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria, but many children do not meet those criteria, especially duration criteria; irritable mood more common than elevated mood (speaker opines that ele­vated mood rare in children, particularly younger children); sleep may not be disturbed; adult symptoms of gran­diosity, excessive spending, and hypersexuality not easily defined in children and difficult to assess; episodicity not typically seen in children; symptoms not described in adult DSM-IV criteria (eg, chronic mania or baseline manic-like state, ultrarapid cycling, ultradian cycling, affective storm) sometimes attributed to juvenile mania

Symptom overlap: manic and hypomanic symptoms overlap with other psychiatric disorders, and comorbidity “is the rule, not the exception”; affective instability often seen in Cluster B personality disorders (although personal­ity disorders not often diagnosed in young people); sleep problems seen in many psychiatric and medical disor­ders

Symptoms unique to BPAD: Geller  —  grandiosity and elevated mood most linked to bipolar disorder; speaker’s observations  —  flight of ideas, decreased need for sleep, hypersexuality, and increased goal-directed activity more typical

Phenotypes: in early 2000s, narrow, intermediate, and broad phenotypes proposed; speaker opines that increase in di­agnosis largely explained by adoption of terms “inter-mediate” and “broad” phenotypes; narrow phenotype  —meets DSM-IV criteria, including duration and hallmark symptoms of elevated mood and grandiosity, for hypo-mania/mania; intermediate 1 phenotype  —  hallmark symptoms of short duration (1 to 3 days); intermediate 2 phenotype  —  meets DMS-IV duration criteria, with episodic irritable hypomania/mania but without elation; broad phenotype  —  nonespisodic severe irritability and hyperarousal without hallmark symptoms

Problems with phenotypes: no evidence that intermediate and broad phenotypes progress to adult bipolar disorder, whereas narrow phenotype does; most treatment literature and recommendations based on narrow phenotype; bi­polar disorder has known course, prognosis, and stigma, so should patient be given label of broad phenotype when unclear if truly bipolar disorder? do labels of intermediate and broad phenotypes subject patient to risk of aggressive pharmacotherapy with little supporting evidence? does “I’m bipolar” provide patients and parents with excuse for problematic or criminal behavior?

Comorbidity: BPAD more often than not accompanied by other Axis I and Axis II diagnoses; most common include, attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder/conduct disorder (ODD/CD), and anxiety; ADHD most common comorbidity in younger children; substance abuse most common in adolescents; other comorbidities include pervasive developmental disorders (Asperger’s syndrome most frequent)

Assessment: obtain family history (speaker believes negative family history argues against diagnosis of bipolar disor­der); in young people, depressive episodes usually precede hypomanic/manic episodes; factors that predict devel­opment of hypomania/mania include 1) depression with rapid onset, psychomotor retardation, and/or psychosis, 2) family history of affective disorders, especially bipolar disorder, and 3) history of hypomania/mania with antide­pressant treatment; suicide rate high in patients with BPAD, especially during depressed phase, so screen carefully for suicidality; screen for comorbid disorders; exercise caution in giving diagnosis of BPAD to children <6 yr of age (diagnosis and its stigma will probably accompany them for life)

Treatment recommendations: from American Academy of Child and Adolescent Psychiatry (AACAP); based largely on adult data (data for children scanty) and on narrow phenotype

Goals of treatment: ameliorate symptoms; provide education to patient and family; promote treatment adherence to prevent relapse; reduce long-term morbidity; promote normal growth and development

Treatment considerations: many drugs used off label in children;  lithium has Food and Drug Administration (FDA) approval for children ³12 yr of age; risperidone (Risperdal) and aripiprazole (Abilify) approved for use in chil­dren ³10 yr of age only for mania or mixed states; most medication trials in youth open label; most required res­cue medications for aggression, psychosis, and sleep disturbance; only 5 published placebo-controlled studies; data suggest that manic switch can be induced by antidepressants (same as in adults); some studies report wors­ening of mania with stimulants; atypical antipsychotics helpful in BPAD alone or in combination with other med­ications; for maintenance therapy, traditional mood stabilizers did not show promise; no published studies exist for combination therapy; few studies looked at comorbidity other than ADHD

Recommendations for somatic treatment: pharmacotherapy primary treatment in well-established bipolar type 1; multiple agents sometimes required, but avoid polypharmacy whenever possible

Begin with FDA-approved treatment for adults: lithium  —acute mania, maintenance therapy; valproate, ris-peridone, olanzapine, quetiapine, ziprasidone, aripiprazole  —  acute mania, mixed state; lamotrigine, olanzapine  —  maintenance; carbamazepine  —  acute mania, mixed state; olanzapine plus fluoxetine  — bipolar depression

Other medications: controlled studies have not found gabapentin or topiramate useful in adults; no evidence that other new agents (eg, tiagabine, oxcarbazepine, zonisamide) effective in bipolar disorder; benzodiazepines helpful as adjunctive treatment in adults, but youth should be monitored  for disinhibition; antidepressants use­ful for depressive symptoms in adults when used in combination with mood stabilizer; be aware of warnings related to antidepressant use in youth; stimulants may be helpful once mood symptoms controlled with mood stabilizer; lamotrigine (Lamictal) has place in treatment of teenagers because it generally causes no weight gain; however, patient must be monitored for serious and life-threatening rash, including Stevens-Johnson syn­drome

Other considerations: most youth with bipolar type 1 require ongoing medication therapy to avoid relapse, and some individuals need lifelong treatment; maintain medication regimen for 12 to 24 mo; when tapering medi­cations in stable patients, close monitoring required; patients and families should be educated about signs and symptoms of relapse; treatment should be resumed quickly if relapse occurs; drug trials should be of adequate dose and duration; patient should be monitored as recommended for side effects and adverse events specific to medications being taken; electroconvulsive therapy (ECT) can be used for patients with narrow phenotype who are severely impaired by depressive or manic episodes

Psychotherapeutic interventions: important component of comprehensive treatment plan for early-onset bipolar dis­order; include psychoeducation, relapse prevention, and social and family functioning

Stress and Anxiety Disorders

R. Bruce Lydiard, MD, PhD, Staff Psychiatrist, Ralph H. Johnson Veterans Affairs Medical Center, and Department of Psy­chiatry and Behavioral Sciences, Medical University of South Carolina, Charleston

Introduction: anxiety typically begins before depression; appearance of second disorder predicts chronicity, and presence of ³2 disorders makes outlook worse, treatment more difficult, and responses slower; anxiety and depres­sion, which precede other psychiatric disorders »70% of time, become risk factors for developing other psychiatric disorders within 6 mo; anxiety disorders more closely associated than depression with onset and persistence of chronic pain

What prevents remission of anxiety and depression? psychiatric comorbidity; medical comorbidity; psychosocial stress; inherited vulnerability; insufficient intensity of treatment likely most important factor

Stress: defined as perceived threat or challenge and perceived inability to overcome or control it; anxiety and mood disorders increase vulnerability to stress and act as stressors

Homeostasis vs allostasis: homeostasis refers to maintenance of stability in certain physiologic parameters, such as body temperature, plasma pH, blood glucose, and oxygen partial pressure; allostasis (also called stress response) refers to recruitment of all available physiologic, psychologic, and behavioral resources to promote survival; op­timally, stress response occurs, crisis resolves, and body returns to homeostasis; however, repeated or chronic stress accrues allostatic load; individual remains perpetually outside of homeostatic parameters, with loss of ef­fective functioning of hypothalamic-pituitary-adrenal (HPA) axis

Interaction of medical and psychiatric disorders: psychiatric disorders characterized by speaker as inflammatory conditions resulting in loss of effective HPA feedback control; caused by excessive corticotropin-releasing hor­mone activity, unrestrained norepinephrine release, uncontrolled release of proinflammatory cytokines, and, ulti­mately, progressive sensitization (eg, neural, emotional, immune system); however, HPA feedback control substantially normalized by effective antidepressant therapy; anxiety disorders contribute to allostatic load equally and independently of depression

Regulation of HPA axis: inhibitory control exerted by hippocampus and prefrontal cortex; stimulatory control ex­erted by amygdala and brainstem monoamine projections; anxiety-depression-stress results in excessive HPA-corticotropin-releasing factor (CRF) activity, which leads to uncontrolled release of stress mediators; sustained HPA-axis activity affects somatosensory response, cardiovascular system, metabolic processes (including bone density), neurodegeneration of frontal cortex, possible shrinkage of hippocampus, and worsening of memory; hy­pocortisolemia increases susceptibility to autoimmune disorders, and hypercortisolemia increases susceptibility to infectious disorders

Sex differences in stress and anxiety disorders: anxiety disorders and depression twice as common in women as in men; speaker opines increase in depression in women largely due to increase in anxiety disorders; differences oc­cur in HPA-axis activity; posttraumatic stress disorder (PTSD) twice as common in women as in men, indepen­dent of degree of stressor; during periods of  stress, women more likely to have exacerbation of other psychiatric disorders; gender differences in response to acute stress  —  women exhibit desire to affiliate, while men exhibit aggression

Anxiety and depression: pathophysiology overlaps with that of migraine, fibromyalgia, chronic fatigue, and various functional gastrointestinal disorders; researcher noted that all these disorders, plus anxiety and depression, re­spond to antidepressants and termed them collectively “affective spectrum disorder group”; family study showed that these disorders run in pedigrees as single risk factor; all involve pain and stress sensitization, and all feature problem of distorted afferent functioning

Anxiety and long-term health: epidemiologic study found 2- to 6-fold increase in medical disorders among those who had anxiety disorder vs those who did not; in about half of those with anxiety disorder, anxiety disorder pre­ceded medical disorder and in other half, medical disorder preceded anxiety disorder, suggesting bidirectional ef­fect; National Comorbidity Study showed association between generalized anxiety disorder (GAD) and hypertension, arthritis, asthma, ulcers, and other gastrointestinal disorders, and researcher suggested that “nearly all of [the impairment] can be attributed to the generalized anxiety disorder”

Negative emotions and immune activation: “ … [There is] a spectrum of diseases whose onset and course may be influenced by proinflammatory cytokines, from cardiovascular disease to frailty and functional decline; proin­flammatory cytokine production can be directly stimulated by negative emotions and stressful experiences” (Kiecolt-Glaser)

Comorbidity with medical disorders connected to cytokine production: insulin resistance; leptin resistance; chronic obstructive pulmonary disease (COPD); functional gastrointestinal disorders; cancer; cardiovascular disorders; autoimmune disorders; chronic pain; infectious diseases

Effects of treatment: antidepressants  —  normalize HPA-axis functioning; alter neuronal gene transcription; have anti-CRF activity; normalize glucocorticoid signaling efficiency; reduce proinflammatory cytokines; reduce circu­lating norepinephrine and epinephrine; cognitive behavioral therapy (CBT)  —  anti-inflammatory effects have not been measured, but on brain scans, changes seen with CBT overlap with changes seen with antidepressants; targets maladaptive chains of thought, feelings, and behaviors; focuses on patient’s learning to monitor and correct cata­strophic thought patterns; biologically active, producing changes in cerebral blood flow

Benzodiazepines: not for treatment of depression; use in anxiety less controversial since benzodiazepines no longer protected by patent; addiction specialists tend to dislike benzodiazepines because of potential for abuse, but anxiety specialists report very little abuse among people with anxiety disorders; combining benzodiazepine with other ben­zodiazepine or with antidepressant shown to be efficacious

Take-home messages: mood and anxiety disorders and overlapping somatic inflammatory conditions share basis in HPA-axis dysfunction (“chicken or egg” situation); variably responsive to antidepressant treatment; anxiety and de­pression represent significant health risks; remission possible with appropriate dose, duration, and documentation of treatment

Suggested Reading

Ballenger JC et al: International Consensus Group on Depression and Anxiety. Consensus statement on depression, anxiety, and functional gastrointestinal disorders. J Clin Psychiatry 62:48, 2001; Charney DS: Psychobiological mechanisms of resilience and vulnerability: implications for successful adaptation to extreme stress. Am J Psychiatry 161:195, 2004; Heimberg H et al, eds: Gen­eralized Anxiety Disorder: Advances in Research and Practice. New York: Guilford Press, 2004; Kalmar JH et al: Relation between amygdala structure and function in adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry 48:636, 2009; Kessler RC et al: Prevalence, comorbidity, and service utilization for mood disorders in the United States at the beginning of the twenty-first cen­tury. Annu Rev Clin Psychol 3:137, 2007; KiecoldtGlaser JK et al: Psychoneuroimmunology and psychosomatic medicine: Back to the future. Psychosom Med 2002, 64:15; Leibenluft E et al: Defining clinical phenotypes of juvenile mania. Am J Psychiatry 160:430, 2003; Lewinsohn PM et al: Bipolar disorder during adolescence and young adulthood in a community sample. Bipolar Disord 2:281, 2000; Lydiard RB: Worried sick: antidepressants, stress, and inflammation. J Clin Psychiatry 68:1613, 2007; McClel­lan J et al: Work Group on Quality Issues. Practice parameter for the assessment and treatment of children and adolescents with bipo­lar disorder. J Am Acad Child Adolesc Psychiatry 46:107, 2007; Pavuluri et al: Pediatric bipolar disorder: a review of the past 10 years. J Am Acad Child Adolesc Psychiatry 44:846, 2005; Pollak Y, Yirmiya R: Cytokine-induced changes in mood and behaviour: implications for ‘depression due to a general medical condition,’ immunotherapy and antidepressive treatment. Int J Neuropsycho­pharmacol , 5:389, 2002; Raison CL, Miller AH: When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders. Am J Psychiatry 160:1554, 2003; Roy-Byrne PP et al: Anxiety disorders and comor­bid medical illness. Gen Hosp Psychiatry 30:208, 2008; Youngstrom EA et al: Comparing the diagnostic accuracy of six potential screening instruments for bipolar disorder in youths aged 5 to 17 years. J Am Acad Child Adolesc Psychiatry 43:847, 2004.