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Program Written Summary
Audio-Digest Psychiatry
Volume 41, Issue 18
September 21, 2012

Definition; Global burden; Major depression; Diagnosis; Augmentation; Alternative therapies; Sleep–related disorders – Philip G. Janicak, MD
From Current Psychiatry/AACP 2012 Psychiatry Update: Solving Clinical Challenges, Improving Patient Care, presented by Current Psychiatry and American Academy of Clinical Psychiatrists, and jointly sponsored by Duke University School of Medicine and Quadrant HealthCom Inc.
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The following is an abstracted summary, not a verbatim transcript, of the lectures/discussions on this audio program.

Psychiatry Program Info  Accreditation InfoCultural & Linguistic Competency Resources

Pharmacologic Therapy for Depression and Anxiety

From Current Psychiatry/AACP 2012 Psychiatry Update: Solving Clinical Challenges, Improving Patient Care, presented by Current Psychiatry and American Academy of Clinical Psychiatrists, and jointly sponsored by Duke University School of Medicine and Quadrant HealthCom Inc.

Philip G. Janicak, MD, Professor of Psychiatry, Rush Medical College, Chicago, IL

Educational Objectives

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

1. Recognize common causes of treatment failure in patients with depression and anxiety.

2. Prevent misdiagnosis in patients with depressive symptoms.

3. Conduct adequate trials of pharmacologic treatments for patients with anxiety and depression.

4. Treat patients with obsessive-compulsive disorder.

5. Target less well-known neurotransmitter systems implicated in depression.

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 following has been disclosed: Dr. Janicak receives grant/research support from Cervel Neurotech, Janssen Pharmaceuticals, Neuronetics, Otsuka, and Sunovion Pharmaceuticals; and is on the Speakers’ Bureaus of Bristol-Myers Squibb, Neuronetics, and Otsuka. The planning committee reported nothing to disclose. In his lecture, Dr. Janicak discusses the off-label or investigational use of a therapy, product, or device.

Background on major depression: depression as symptom — manifests in many different disorders; must be distinguished from depressive disorders (since, eg, patients with bipolar disorder [BD] often present with symptoms identical to unipolar major depressive disorder [MDD] and thus receive inappropriate treatment); relatively subtle forms of mood instabilityeg, cyclothymic disorder and dysthymia (may occur independently or as comorbidity with major depressive syndromes)

Depressive symptoms vs depressive mindset: transcranial magnetic stimulation has produced dramatic improvements in depressive symptoms that have persisted for 6 to 8 yr; however, patients with longstanding symptoms often establish lifestyle-related expectations associated with chronic unremitting depression (eg, impaired self-esteem, social discomfort); remediation of symptoms of may not resolve disabilities associated with ongoing chronic issues; in many circumstances, chronic disabilities require nonpharmacologic treatment (eg, supportive therapy, cognitive behavioral therapy)

Depressive personality traits: common; often more amenable to nonpharmacologic approaches

Diagnosis of clinical depression: often misdiagnosed due to overlap with BD, anxiety disorders, and comorbid medical conditions (potential bidirectional cause, since, eg, patients with MDD have higher rates of cardiovascular disease and certain cancers); 70% of patients can respond to appropriate medications, but drug trials inadequate in many cases

Treatment response vs remission: to receive regulatory approval, medications required to produce only 50% reduction in symptoms; however, physicians strive to achieve goal of remission (as defined by adequate scoring on rating scales); most current medications have limited efficacy for achieving remission and have not been assessed in context of their ability to do so

Adequate trials: according to Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, many medications require dosages considered high or in excess of recommendations (eg, daily average of 42 mg of citalopram [2 mg above recommended maximum]) and longer treatment durations (eg, 12-14 wk with citalopram) before producing remission; speaker recommends communicating expectations with patient and monitoring symptoms closely during 3- to 5-wk trials; patients with even partial quantifiable responses during trial should continue with regimen; patient’s subjective sense of wellbeing may be last symptom to show improvement

Measurement-based medicine: increasingly required as condition of reimbursement for physicians; proven to improve care

Barriers to remission: lack of perceived improvement; adherence issues; insufficient funds; failure to discuss treatment issues; comorbidities (psychiatric and medical); safety issues and poor tolerability preventing adequate trials

Treatment-resistant depression (TRD): commonly defined as lack of response to 2 adequate trials of antidepressants during same episode; seen in 20% to 30% of patients with MDD; often caused by inaccurate diagnosis, failure to achieve remission, inadequate assessment of response per measurement-based care, or psychosocial factors

Management of TRD: clarify diagnosis (by, eg, assessing for mood instability disorders in younger patients with history of multiple episodes of depression and failed trials); increase dose or duration of treatment (combined with ascertainment of adherence; only 20%-25% of attempted trials genuinely reach adequacy [often due to adherence issues]); switch within or across classes of antidepressants (strategies showed similar efficacy in STAR*D); combination therapy (ie, adding agent to address specific symptom) or augmentative therapy (ie, attempting to boost efficacy of existing medications against core depressive symptoms)

Advantages of augmentation: useful in patients with refractory depression who show partial responses to existing regimens; response more rapid (relative to switching); maintains initial partial response; no time lost

Disadvantages of augmentation: potential interactions between medications and related increases in adverse effects; increased costs; decreased adherence

Augmentation strategies: buspirone — partial agonist of 5-hydroxytryptamine (5-HT)1a serotonin receptors; shown to improve depression over longer exposure to antidepressant; pindololβ-blocker with antagonist affinity for 5-HT1a receptors; may rapidly increase serotonin (and thus provoke more rapid responses to antidepressants); second generation antipsychotics (SGAs) — only approved strategies aripiprazole and quetiapine; some agents (particularly quetiapine) show efficacy as monotherapy (in patients without psychotic depression)

Targeting monoamine systems: medications showing partial or full agonism of 5-HT1a receptor may be effective in combination pharmacotherapy; newest approved antidepressant (vilazodone [Viibryd]) acts as selective serotonin reuptake inhibitor (SSRI), but also as partial agonist at 5-HT1a receptor (thought to increase rapidity of response); newer antipsychotics (AP) appear to moderate depression through antagonist properties at 5-HT2a 5-HT2c and 5-HT7 (asenapine only) receptors; dopamine — often overlooked, but critical for regulation of reward systems affected by depression (ie, anhedonia); many clinicians have attempted combining partial agonists of dopamine receptor 2 (D2) and D3 (eg, pramipexole) with standard antidepressants; triple reuptake inhibitors — increase availability of serotonin, dopamine, and norepinephrine; eg, monoamine oxidase inhibitors

Targeting glutamate systems: studied in many pathophysiologic disorders in psychiatry (eg, schizophrenia), as well as in depression and anxiety; glutamate acts as primary excitatory neurotransmitter in central nervous system; carries signals from cortical emanations to key structures of brain (eg, ventral tegmental area) and modulates activity of many other neurotransmitters; receptor subtypes — ionotropic receptors (eg, N-methyl-D-aspartic [NMDA] acid, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, kainate receptors); metabotropic receptors (all studied subtypes have shown potential antidepressive effects)

Ketamine: promising and increasingly studied treatment for unipolar and bipolar TRD; used as tranquilizer and anesthetic for several decades; small primarily open-label studies have shown dramatic but typically short-lived improvements; has many downsides (eg, potential for induced psychosis); even extremely careful dosing may cause difficulties; may adversely affect cognition; studied as single infusion and with multiple doses over time to maintain effect (benefits of single dose does not typically persist for >2 wk); effects at NMDA receptor result in positive changes in many neurotransmitter systems implicated in depression and corticolimbic mood circuit; post hoc data indicate rapid decreases in suicidal ideation (in addition to depression); potentially useful during period before antidepressants have taken effect; dosing — typically 0.5 mg/kg given intravenously (IV) over 40-min period

Targeting cholinergic systems: overactive cholinergic systems may contribute to depressive symptoms and dysregulation of key neurotransmitters; receptor subtypes — muscarinic and nicotinic (both ionotropic); treatments — scopolamine shows many antidepressive properties, but carries many risks due to nonselective effects on muscarinic receptors; new agents selectively targeting muscarinic receptor subtypes 1 to 5 may achieve antidepressant benefits without side effects (particularly cognitive deficits); nicotinic receptor modulators — nicotine shows evidence of efficacy in inducing positive mood states (particularly when inhaled); agents targeting various nicotinic subsystems (eg, mecamylamine, S-(+)-mecamylamine [TC-5214]) have been shown to modulate neurotransmitters implicated in depression, but efficacy trials have had mixed to poor outcomes

Targeting melatonergic symptoms: sleep-wake cycle disturbances frequently manifest with depression, and stabilization of these disturbances improves mood states; bright-light therapy and medications (eg, agomelatine) can affect overall melatonin expression through superchiasmatic nucleus of brain (ie, “internal clock”), and thereby restore sleep-wake cycles; however, agomelatine has shown mixed results and potential hepatic toxicity in studies, and remains unapproved in United States; ramelteon (Rozerem) — melatonin receptor subtype 1 and 2 agonist; sedative-hypnotic agent; effective in select patients

Targeting glucocorticoid systems: many investigations have assessed role of stress diathesis in depression and potential efficacy of glucocorticoid antagonism (with, eg, mifepristone) in improving depressive syndromes (particularly psychotic depression); mifepristone — found to remediate psychotic features of depression in absence of antipsychotic medications; recent data indicates superior results with plasma concentrations >60 ng/mL (possible explanation for mixed study outcomes)

Omega-3 fatty acids: in studies, large doses appear to positively affect mood states; however, randomized controlled trials have mixed outcomes (potentially due to different ratios of eicosapentaenoic acid [EPA] to decosahexaenoic acid [DHA]); supplements must contain 60% EPA to achieve antidepressant effects

Levomefolic acid: meta-analysis found insufficient evidence for widespread recommendation; medical food indicated for use as adjunct to antidepressants in unresponsive depressed patients who have low levels of folic acid (data indicate reduced efficacy in those with adequate folic acid)

D-Cycloserine for anxiety: novel treatment used to moderate patient’s receptivity to psychotherapy (eg, cognitive psychotherapeutic interventions)

APs for anxiety: use doubled between 2004 and 2007 despite absence of evidence supporting efficacy; in meta-analysis of randomized controlled trials, augmentation with first- and second-generation APs failed to surpass placebo; however, some data supported superiority of extended-release quetiapine over placebo; significant risks associated with SGAs may outweigh potential benefits in patients with mood disorders; recent studies have shown greater motor neurotoxicity and metabolic disturbances when given to patients with anxiety (compared to patients with schizophrenia or BD)

Pregabalin (Lyrica): approved for pain syndromes and seizure disorders in United States; found to be superior to placebo and lorazepam in 5 large well-controlled studies for generalized anxiety disorder and one large study for social anxiety disorder; supported by much stronger evidence than gabapentin; lacks disadvantages associated with benzodiazepines (eg, habituation, dependency) and serotonergic agents

Eszopiclone: found to reduce sleep disturbances and primary symptoms (eg, re-experiencing, arousal) associated with posttraumatic stress disorder

Obsessive-compulsive disorder (OCD): data indicate more optimal effects with extremely high doses of SSRIs (eg, 400 mg of sertraline; contraindicated with citalopram due to potential prolongation of Q-T interval and cardiac rhythm disturbances); clomipramine (Anafranil) — IV formulations found to be effective in patients unresponsive to oral dosing; APs — haloperidol and risperidone have strongest evidence; glutamatergic therapies — difficult to implement (overly aggressive or direct approaches may cause neuronal excitation and death); most agents target glycine receptors (colocated with NMDA receptor) to provide more indirect and gentle effects; augmentation with APs — meta-analysis found SSRIs plus SGAs superior to SSRIs alone for severe refractory OCD; however, nearly all studies of APs as monotherapy had negative outcomes; APs appear to have superior benefits in patients with comorbid tic disorders

Narcolepsy: rare condition; primarily presents as excessive daytime sleepiness (EDS), but may cause sudden muscle loss associated with intense emotions, sleep paralysis, hypnogogic or hypnopompic phenomena, and sleep fragmentation; associated with deficiency in hypocretin (neuropeptide) caused by selective loss of specific cell type in lateral hypothalamus; sodium oxybate (Xyrem) successfully manages cataplexy and EDS; prescribing requires specialized training and registration (due to potential for abuse and strict regulation), plus careful patient selection; 7-yr study found low rates of abuse, overdosing, and misuse in sexual assaults; dosing — varies between 3 and 9 g daily; must be mixed with sweetened liquid (to disguise taste) and split into 2 doses (due to short half-life)

Questions and Answers

Levomefolic acid: measurement of endogenous levels indicated before using as treatment (only effective in deficient individuals)

Bromocriptine for augmentation of antidepressants: some studies have had positive findings (similar to other D2 receptor agonists); high doses may cause adverse effects (including psychotomimetic reactions)

Adult attention-deficit hyperactivity disorder (ADHD) mimicking TRD: 50% of patients with ADHD have comorbid BD, and medications used for ADHD may (paradoxically) treat mania in BD (possibly by increasing activity in inhibitory regions of brain)

Cardiac side effects of escitalopram (Lexapro) and citalopram: in STAR*D, no Q-T prolongation seen with doses of citalopram >40 mg; however, extremely high doses (80 mg) may have such effects; no evidence of Q-T prolongation found with escitalopram

Combination therapies for pain disorders: many medications indicated for anxiety also have indications for, eg, fibromyalgic and neuropathic pain (eg, pregabalin, duloxetine); pain syndromes often occur as comorbidities with depression any may be exaggerated by depressive syndromes

Modafinil (Provigil) and armodafinil (Nuvigil) for narcolepsy: approved and indicated for EDS associated with narcolepsy


Dr. Janicak spoke at Current Psychiatry/AACP 2012 Psychiatry Update: Solving Clinical Challenges, Improving Patient Care, held March 29-31, 2012, in Chicago, IL, presented by Current Psychiatry and the American Academy of Clinical Psychiatrists, and jointly sponsored by Duke University School of Medicine and Quadrant HealthCom Inc. For information about next year’s Psychiatry Update, visit The Audio-Digest Foundation thanks Dr. Janicak and the sponsors for their cooperation in the production of this program.

Suggested Reading

Anand A, Matthew SJ: Ketamine treatment for major depression.Psychopharm Rev 46:89, 2011; Comer JS et al: National trends in the antipsychotic treatment of psychiatric outpatients with anxiety disorders. Am J Psychiatry 168:1057, 2011; Dattilo NC et al: D-Cycloserine augmentation of cognitive-behavioral therapy for the treatment of anxiety disorders. Psychopharm Rev 46:49, 2011; Jefferson JW: Folate for depression. Psychpharm Rev 42:75, 2007; Krystal H et al: Adjunctive risperidone treatment for antidepressant-resistant symptoms of chronic military service-related PTSD. JAMA 306:493, 2011; LaLonde CD, Van Lieshout RJ: Treating generalized anxiety disorder with second generation antipsychotics. J Clin Psychopharmacol 31:326, 2011; Li X et al: Review of pharmacological treatment in mood disorders and future directions for drug development. Neuropsychopharmacology 37:77, 2012; Lippiello PM et al: TC-5214 (S-(+)-mecamylamine): a neuronal nicotinic receptor modulator with antidepressant activity. CNS Neurosci Ther 14:266, 2008; Pack Al, Pien GW: Update on sleep and its disorders. Annu Rec Med 62:24, 2011; Pollack MH et al: Eszopiclone for the treatment of posttraumatic stress disorder and associated insomnia. J Clin Psychiatry 72:892 2011; Ravindran LN, Stein MB: The pharmacologic treatment of anxiety disorders. J Clin Psychiatry 71:839, 2010.

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