Clinical and pharmacologic perspectives on the treatment of major depressive disorder.

Major depressive disorder (MDD) is commonly encountered in clinical practice but is often underdiagnosed and undertreated, in part because many patients present only with vague somatic complaints instead of typical depressed symptomatology. Once diagnosed, patients with MDD can be treated with pharmacologic and/or nonpharmacologic therapies, but it is difficult to predict how or whether an individual will respond. Studies have shown that the majority of depressed patients fail to remit with initial therapy and, even if remission is achieved, many patients will relapse. While the management of patients with MDD presents challenges, data indicate that the achievement and maintenance of remission can be improved by frequent follow-ups with a clinician who can provide individualized education/support and appropriate referral to other healthcare specialists. Novel pharmacotherapies that are formulated for oncedaily dosing with improved safety profiles can improve adherence to treatment and reduce the morbidity and mortality associated with MDD.

Bupropion for major depressive disorder: Pharmacokinetic and formulation considerations.

BACKGROUND: Major depressive disorder (MDD) is a common psychiatric condition, with 6.6% of the adult population in the United States experiencing a major depressive episode during any given year. Depressed patients must receive adequate treatment to maximize the likelihood of clinical success. Bupropion hydrochloride, a noradrenergic/dopaminergic antidepressant, is available in 3 oral formulations: immediate release (IR) (given TID), sustained release (SR) (given BID), and extended release (XL) (given QD). Understanding the pharmacokinetic (PK) properties and formulations of bupropion can help optimize clinical use. OBJECTIVES: : The aims of this article were to provide a review of the PK properties of bupropion and identify its various formulations and clinical applications to help optimize treatment of MDD. METHODS: : In this review, data concerning PK trials/reports were collected from articles identified using a PubMed search. The search was conducted without date limitations and using the search terms bupropion, bupropion SR, bupropion XL, bupropion pharmacokinetics, bupropion metabolism, and bupropion drug interactions. Additional reports were selected from references that appeared in articles identified in the original search. In addition, data from studies summarized in product information and labeling were obtained. All available information, concentrating on studies in humans, pertinent to bupropion PK properties and/or formulations was included. RESULTS: : Bupropion is extensively metabolized by the liver (t(1/2), approximately 21 hours). Hydroxybupropion, the primary active metabolite (t(1/2), approximately 20 hours), is formed by cytochrome P450 (CYP) 2B6. At steady state, C(max) of hydroxybupropion is 4- to 7-fold higher, and the AUC is approximately 10-fold greater, compared with those of the parent drug. Threohydrobupropion and erythrohydrobupropion (mean [SD] t(1/2) values, approximately 37 [13] and approximately 33 [10] hours, respectively), the other active metabolites of bupropion, are formed via nonmicrosomal pathways. Relative to bupropion, the C(max) values are approximately 5-fold greater for threohydrobupropion and similar for erythrohydrobupropion. Based on a mouse antitetrabenazine model, hydroxybupropion is approximately 50% as active as bupropion, and threohydrobupropion and erythrohydrobupropion are approximately 20% as active as bupropion. Bupropion lowers the seizure threshold and, therefore, concurrent administration with other agents that lower the seizure threshold should be undertaken cautiously. Potential interactions with other agents that are metabolized by CYP2B6 should be considered. In addition, bupropion inhibits CYP2D6 and may reduce clearance of agents metabolized by this enzyme. Absorption of the XL formulation is prolonged compared with the IR and SR formulations (T(max), approximately 5 hours vs approximately 1.5 and approximately 3 hours, respectively). Bupropion is dosed without regard to food. CONCLUSIONS: : Understanding the PK profile and formulations of bupropion can help optimize clinical use. Bupropion is metabolized extensively, resulting in 3 active metabolites. This metabolic profile, various patient factors (eg, age, medical illnesses), and potential drug interactions should be considered when prescribing bupropion. The 3 formulations-bupropion, bupropion SR, and bupropion XL-are bioequivalent and offer options to optimize treatment for patients with MDD.

Lamotrigine in psychiatry: pharmacology and therapeutics.

Following the introduction of lamotrigine in 1994 as a treatment for epilepsy in the United States, the drug has seen progressively greater application in psychiatry, particularly as a treatment for bipolar disorder. This review critically evaluates the support for lamotrigine use across a broad range of psychiatric disorders as well as discuss its pharmacology, side-effect profile, and interactions with other medications.

Psychiatric complications of deep brain stimulation for Parkinson's disease.

BACKGROUND: The purpose of this article is to review the current literature regarding deep brain stimulation (DBS) of the subthalamic nucleus as a treatment for Parkinson's disease and to bring to the attention of the psychiatric community the possible psychiatric complications of this treatment. METHOD: A MEDLINE search of English-language publications was conducted using PubMed in July 2003. The search term used was deep brain stimulation. In addition, pertinent references were obtained from the retrieved articles. Reports and studies of psychiatric complications of DBS patients were reviewed and are discussed. A case report is presented of a man who developed hypomanic symptoms shortly after beginning DBS treatment for Parkinson's disease. RESULTS: There have been an increasing number of reports of postprocedure psychiatric complications, including depression, mania, aggression, and deficits in language. Improvement in symptoms of severe obsessive-compulsive disorder and depression has also been reported. CONCLUSION: As information continues to emerge, psychiatrists will play vital roles in the assessment and continuing care of patients who receive DBS. These findings may also provide the framework to determine which patients are at psychiatric risk from DBS. Symptoms of refractory obsessive-compulsive disorder have been noted to improve with DBS, which has led researchers to begin studying its effectiveness for this condition.

Social Anxiety Disorder: More Than Just a Little Shyness.

Social anxiety is defined as a "marked and persistent fear of social or performance situations" and includes such symptoms as sweating, palpitations, shaking, and respiratory distress. Social anxiety is fairly common, occurring in as much as 13% of the population, and can be extremely disabling. It can be either specific (confined to 1 or 2 performance situations) or generalized, and can be diagnosed with a scale-based questionnaire. Social anxiety may coexist with other disorders, such as depression and dysthymia. The differential diagnosis for social anxiety includes panic disorder, agoraphobia, atypical depression, and body dysmorphic disorder. Treatment for social anxiety can be quite effective and consists of psychotherapy, pharmacotherapy (including such medications as beta-blockers, anxiolytics, antidepressants, and anticonvulsants), or a combination. This article details the prevalence, onset, disease impact, and etiology of social anxiety. Specific treatments, including both psychotherapy and pharmacotherapy, are presented in detail, along with other treatment considerations, such as comorbidity.

Predictive Value of Baseline Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) Assessments for Identifying Risk of Prospective Reports of Suicidal Behavior During Research Participation.

OBJECTIVE: Examine the ability of baseline electronic Columbia-Suicide Severity Rating Scale lifetime suicidal ideation and behavior categories to predict prospective reports of suicidal behavior in psychiatric and non-psychiatric research participants. DESIGN: Meta-analysis of 74,406 eC-SSRS assessments completed between September 2009 and December 2012. SETTING: Thirty-three clinical research studies that used the electronic Columbia-Suicide Severity Rating Scale to assess suicidal ideation and behavior at baseline and prospectively during follow-up visits. PARTICIPANTS: Records from 6,760 patients with psychiatric disorders (opioid dependence, generalized anxiety, major depressive, and posttraumatic stress disorders) and 2,077 nonpsychiatric disorder patients (chronic obstructive pulmonary disease, epilepsy, fibromyalgia, human immunodeficiency virus, insomnia, multiple sclerosis, osteoarthritis, pain/back pain, Parkinson's disease, restless leg syndrome) were analyzed. MEASUREMENTS: Electronic Columbia-Suicide Severity Rating Scale assessment of lifetime suicidal ideation (5 severity levels) and suicidal behavior (4 types) at baseline and prospectively reported suicidal behavior during study participation. RESULTS: Increasingly more severe lifetime suicidal ideation at baseline was associated with a progressively greater likelihood of prospectively reported suicidal behavior during study participation. Intent to act on suicidal ideation was most predictive of reports of suicidal behavior. Reports of lifetime suicidal behaviors at baseline also predicted subsequent suicidal behavior, and multiple lifetime behaviors monotonically increased prospective risk of suicidal behavior. Baseline suicidal ideation and behavior predicted future suicidal behavior in both psychiatric and non-psychiatric trials. CONCLUSIONS: Lifetime reports of suicidal ideation and/or behavior at baseline significantly increased risk of prospectively reporting suicidal behavior during research trial participation in both psychiatric and nonpsychiatric patients. Lifetime prevalence of suicidal ideation and behavior is higher among psychiatric patients, but also presents a safety concern among nonpsychiatric patients when reported.

Prediction of suicidal behavior in clinical research by lifetime suicidal ideation and behavior ascertained by the electronic Columbia-Suicide Severity Rating Scale.

OBJECTIVE: To evaluate whether lifetime suicidal ideation with intention to act and/or suicidal behaviors reported at baseline predict risk of prospectively reporting suicidal behavior during subsequent study participation. METHOD: Data from studies using the electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) to prospectively monitor suicidal ideation and behaviors between September 2009 and May 2011 were analyzed. Studies included patients with major depressive disorder, insomnia, posttraumatic stress disorder, epilepsy, and fibromyalgia. Records for 35,224 eC-SSRS assessments were extracted. Incomplete assessments and eC-SSRS records from patients missing a baseline assessment or with no prospective follow-up assessments were excluded. Baseline lifetime eC-SSRS reports were categorized as negative (no lifetime ideation with intent to act or prior suicidal behavior) or positive (lifetime ideation with intent to act but no prior behavior, no ideation with intent to act but prior behavior, or both lifetime ideation with intent and prior behavior). RESULTS: 3,776 patients completed a baseline and 1 or more follow-up assessments. The mean follow-up period was 64 days. Of patients with negative lifetime reports, 2.4% subsequently reported suicidal behavior during study participation, compared to 12.0% of patients with lifetime ideation with intent only (OR = 5.55; 95% CI, 2.65-11.59), 9.6% of patients with lifetime behavior only (OR = 4.33; 95% CI, 2.94-6.39), and 18.3% of patients with both (OR = 9.13; 95% CI, 6.47-12.88). Sensitivity and specificity of positive reports for identifying suicidal behaviors were 0.67 and 0.76, respectively. CONCLUSIONS: Patients reporting lifetime suicidal ideation with intent to act and/or prior suicidal behavior at baseline are 4 to 9 times more likely to prospectively report suicidal behavior during study participation.

A clinician's guide to monitoring kidney function in lithium-treated patients.

OBJECTIVE: Bipolar disorder treatment guidelines recommend kidney-function monitoring at regular intervals for patients taking lithium, but they tend not to provide specifics with regard to what to measure and how to ensure that the results most accurately reflect true kidney function. This overview clarifies those practical aspects of monitoring that are often overlooked or misunderstood. DATA SOURCES: Utilized English language materials were obtained by PubMed searches (1970-2009), from the Lithium Information Center database, and from books. Search terms included lithium, kidney function, creatinine, creatinine clearance, GFR, GFR prediction equations, albuminuria, and urine concentration. DATA SYNTHESIS: Urine osmolality most accurately reflects urine concentrating ability, although specific gravity is usually adequate for clinical purposes. Serum creatinine concentration can be influenced by extrarenal factors, but even when these are controlled, it remains a less than ideal measure of glomerular filtration rate (GFR). Prediction equations are used commonly to estimate GFR and are an advance over serum creatinine alone, but even they are not as useful when GFR is only mildly impaired. Urine albumin measurement is important, but it requires greater standardization and sensitivity to maximize its potential. CONCLUSIONS: The safe and effective use of lithium requires regular monitoring of kidney function. Doing so effectively requires knowledge of what to measure, how to ensure accurate results, and how to properly interpret them.

Feasibility and validation of a computer-automated Columbia-Suicide Severity Rating Scale using interactive voice response technology.

OBJECTIVE: To evaluate a computer-automated version of the Columbia-Suicide Severity Rating Scale (C-SSRS) using interactive voice response technology (eC-SSRS™). The eC-SSRS assesses "Lifetime" ideations and behaviors at baseline and monitors suicidality prospectively thereafter. Ten control volunteers and ten psychiatric inpatients participated and were administered the C-SSRS at baseline and 4-8 days later by two experienced clinical trial raters. Study participants also completed the eC-SSRS using touch-tone telephones. Kappa measures of agreement compared inter-rater reliability of the C-SSRS administrations and the C-SSRS administrations with the eC-SSRS. Convergent validity with the Beck Scale for Suicide Ideation BSS and patient feedback forms were also evaluated. Twenty baseline and nineteen follow-up assessments were completed. In general, agreement between the eC-SSRS and each rater was comparable or superior to the agreement between both raters. Subject feedback and personal preferences varied across individuals, but were generally supportive of the feasibility and validity of the eC-SSRS. The reliability and validity of the C-SSRS and eC-SSRS for assessing suicidal ideation and behaviors were comparable in this first study comparing the methods. These data were obtained from relatively small patient samples recruited from a single investigational site over a relatively short follow-up period. They support the feasibility and validity of the eC-SSRS for prospective monitoring of suicidality for use in clinical trials or clinical care, but further research with larger samples, other patient populations, and longer follow-up periods is needed.

Strategies for switching antidepressants to achieve maximum efficacy adolescents.

If a patient with major depressive disorder has not responded after an adequate trial of an antidepressant medication, switching to another antidepressant of the same class or a different class may help. When choosing an alternative antidepressant, clinicians should consider the patient's symptoms, drug preferences, and psychiatric and medical comorbidities, as well as drug tolerability, interactions, mechanisms of action, and cost. A wide range of antidepressants is available from a variety of classes, including selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, norepinephrine and dopamine reuptake inhibitors, tricyclics, and monoamine oxidase inhibitors (MAOIs). From current evidence, it appears that a switch within or between any class is legitimate. When switching between antidepressants, an appropriate switching strategy should be used. Although a sufficient washout period is essential when switching to or from an MAOI, in switches between other classes of antidepressant, no single strategy has proven benefit over another. The direct approach to switching, the crossover approach, the moderate approach, and the conservative approach are all commonly used in clinical practice. Each switch strategy has advantages and disadvantages, and the choice should be made based on the patient, the patient's illness, the medications involved, and clinical judgment.

Bupropion extended-release for depressive disorders.

Bupropion is an antidepressant thought to work through effects on norepinephrine and dopamine. It was first marketed in the USA in 1989 as a thrice-daily immediate-release preparation. This was followed in 1996 by twice-daily sustained-release and, most recently in 2003, by once-daily extended-release preparations. Its clinical efficacy for treating depression is equivalent to that of other antidepressants. In addition, the extended-release preparation has been shown to be effective for treating geriatric depression and depression characterized by reduced energy, pleasure and interest, and for preventing recurrence of seasonal affective disorder. Favorable aspects of its side-effect profile include low likelihood of somnolence, sexual dysfunction and weight gain. This review provides a history of the evolution of bupropion in its three formulations, with an emphasis on the efficacy and tolerability of the extended-release preparation.

Teaching psychopharmacology: what works and what doesn't.

How do we best teach clinical psychopharmacology to trainees and clinicians, so they not only increase their knowledge base, but even more importantly also learn to practice the most informed, evidence-based practice possible? This article attempts to answer this elusive question by compiling the individual and combined wisdom of 5 expert psychopharmacology teachers, each of whom draws on years of their own experiences as master educators. The topics covered include teaching clinical psychopharmacological competence in adult psychiatry residency training and in issues specific to both pediatric and geriatric populations, teaching physicians to improve clinical outcomes through continuing medical education, and new developments in adult-centered pedagogy and assessment. Although the focus of this article is on practical pearls found useful in teaching psychiatric residents and practicing physicians, the lessons learned are applicable to other groups of learners such as medical students, other trainees, and nonmedical clinicians. Our goal is to help educators produce competent psychopharmacology clinicians schooled in the latest evidence, capable of keeping up with new knowledge as it becomes available, and practicing both the art and science of expert clinical care.

Time to response in panic disorder in a naturalistic setting: combination therapy with alprazolam orally disintegrating tablets and serotonin reuptake inhibitors compared to serotonin reuptake inhibitors alone.

OBJECTIVE: This study evaluated time to response in the treatment of panic disorder with a selective serotonin reuptake inhibitor (SSRI) or serotonin norepinephrine reuptake inhibitor (SNRI) combined with alprazolam orally disintegrating tablets (ODT), or SSRI/SNRI alone. DESIGN: Subjects were randomized to eight weeks open-label treatment with alprazolam ODT (4 weeks treatment followed by 3-4 week taper) combined with an SSRI or SNRI, or treatment with SSRI/SNRI alone. SETTING: The study was conducted under naturalistic conditions at 62 primary care and 34 psychiatric practices. PARTICIPANTS: Male or female subjects ≥18 years of age diagnosed with panic disorder, with or without agoraphobia. MEASUREMENTS: The primary efficacy measure was time to response, defined as ≥50-percent decrease from baseline Hamilton Rating Scale for Anxiety (HAM-A) total score. Secondary measures included change from baseline in HAM-A scores and the Clinical Global Impression of Improvement (CGI-I) and Patient Global Impression (PGI) scales. RESULTS: The intent-to-treat (ITT) population comprised 245 subjects. There was no statistical difference between treatment groups in time to response in the ITT population; however, a prospectively defined per protocol analysis revealed a statistically significant earlier onset of effect in subjects receiving SSRI/SNRI plus alprazolam ODT (P<0.05). Mean change from baseline in HAM-A total score and clinician and patient measures of global improvement also showed statistically significant early advantages for combination therapy compared with SSRI/SNRI monotherapy. CONCLUSION: Combined treatment of panic disorder with alprazolam ODT and an SSRI/SNRI may be associated with more rapid improvement in anxiety symptoms compared with an SSRI/SNRI alone.

Extended-release bupropion for patients with major depressive disorder presenting with symptoms of reduced energy, pleasure, and interest: findings from a randomized, double-blind, placebo-controlled study.

OBJECTIVE: This multicenter, double-blind, placebo-controlled study evaluated the efficacy and safety of extended-release bupropion (bupropion XL) in the treatment of major depressive disorder (MDD) with prominent symptoms of decreased energy, pleasure, and interest. METHOD: Eligible adult outpatients meeting DSM-IV criteria for MDD were randomly assigned to bupropion XL 300 to 450 mg/day (N = 135) or placebo (N = 139) for 8 weeks. The primary efficacy measure, change from baseline on the 30-item Inventory of Depressive Symptomatology-Self Report (IDS-IVR-30) total score, was obtained using interactive voice response (IVR) technology. Secondary measures included change from baseline on the 30-item Inventory of Depressive Symptomatology-Clinician-Rated (IDS-C-30) total score and change in domain subset scores for energy, pleasure, and interest; for insomnia; and for anxiety. Response and remission rates were also calculated. Safety was assessed by withdrawal rates, adverse events (AEs), body weight, and vital signs. The study was conducted from June 24, 2003, to June 30, 2004. RESULTS: Bupropion XL was superior to placebo at endpoint in reducing the IDS-IVR-30 total score (p = .018) and the energy, pleasure, and interest domain (p = .007) and the insomnia domain (p = .023) scores. IDS-C-30 outcomes were also significant (p < .001; p < .001, and p = .008, respectively). Clinician-rated remission rates were significantly higher with bupropion XL than placebo (32% vs. 18%, IDS-C-30; 41% vs. 27%, IDS-IVR-30), as were response rates (50% vs. 35%, IDS-C-30; 53% vs. 38%, Clinical Global Impressions-Improvement of Illness). Most AEs were mild or moderate. The incidence of a >or= 7% body weight loss was 3.7% with bupropion XL and 1.4% with placebo. CONCLUSION: Bupropion XL was effective and well tolerated in MDD patients with decreased energy, pleasure, and interest.