An evidence-based approach to psychopharmacology for posttraumatic stress disorder (PTSD) - 2022 update.

Algorithms for posttraumatic stress disorder were published by this team in 1999 and 2011. Developments since then warrant revision. New studies and review articles from January 2011 to November 2021 were identified via PubMed and analyzed for evidence supporting changes. Following consideration of variations required by special patient populations, treatment of sleep impairments remains as the first recommended step. Nightmares and non-nightmare disturbed awakenings are best addressed with the anti-adrenergic agent prazosin, with doxazosin and clonidine as alternatives. First choices for difficulty initiating sleep include hydroxyzine and trazodone. If significant non-sleep PTSD symptoms remain, an SSRI should be tried, followed by a second SSRI or venlafaxine as a third step. Second generation antipsychotics can be considered, particularly for SSRI augmentation when PTSD-associated psychotic symptoms are present, with the caveat that positive evidence is limited and side effects are considerable. Anti-adrenergic agents can also be considered for general PTSD symptoms if not already tried, though evidence for daytime use lags that available for sleep. Regarding other pharmacological and procedural options, e.g., transcranial magnetic stimulation, cannabinoids, ketamine, psychedelics, and stellate ganglion block, evidence does not yet support firm inclusion in the algorithm. An interactive version of this work can be found at www.psychopharm.mobi.

Psychopharmacology of agitation in acute psychotic and manic episodes.

PURPOSE OF REVIEW: To provide updated guidance for the medication treatment of acute agitation in the setting of psychosis or mania on inpatient psychiatric units. RECENT FINDINGS: This topic presented challenges: studies are sparse, tend to be under-powered, and are difficult to compare. Though there have been few recent studies, there have been several recent meta-analyses, Cochrane reviews, and published guidelines that sift through the primarily older evidence as well as more recent trials. The reviewers often do not agree on what seems to have the best evidence for efficacy and safety. SUMMARY: We conclude that the best approach is to summarize in some detail the evidence for each possible treatment and the interpretations published recently on each of those treatments, and then present recommendations for medication management in tiered rankings, based on the authors' qualitative review of the data and opinions. For oral treatment, the first-tier options are (alphabetically) haloperidol with lorazepam, lorazepam alone, and olanzapine. The second tier includes haloperidol with promethazine, loxapine inhaler, and risperidone alone. Tier 3 includes asenapine and quetiapine. For intramuscular treatment, the first-tier includes haloperidol plus promethazine, and olanzapine alone, and the second-tier includes haloperidol with lorazepam, and lorazepam alone.

The Psychopharmacology Algorithm Project at the Harvard South Shore Program: An update on management of behavioral and psychological symptoms in dementia.

Geriatric patients with dementia frequently present with agitation, aggression, psychosis, and other behavioral and psychological symptoms of dementia (BPSD). We present an update of our previously published algorithms for the use of psychopharmacologic agents in these patients taking into account more recent studies and findings in meta-analyses, reviews, and other published algorithms. We propose three algorithms: BPSD in an emergent, urgent, and non-urgent setting. In the emergent setting when intramuscular (IM) administration is necessary, the first-line recommendation is for olanzapine (since IM aripiprazole, previously favored, is no longer available) and haloperidol injection is the second choice, followed by possible consideration of an IM benzodiazepine. In the urgent setting, the first line would be oral second-generation antipsychotics (SGAs) aripiprazole and risperidone. Perhaps next could be then prazosin, and lastly electroconvulsive therapy is a consideration. There are risks associated with these agents, and adverse effects can be severe. Dosing strategies, discontinuation considerations, and side effects are discussed. In the non-emergent setting, medications are proposed for use in the following order: trazodone, donepezil and memantine, antidepressants such as escitalopram and sertraline, SGAs, prazosin, and carbamazepine. Other options with less support but potential future promise are discussed.

The psychopharmacology algorithm project at the Harvard South Shore Program: An algorithm for core symptoms of autism spectrum disorder in adults.

Autism spectrum disorder (ASD) is characterized by impaired social communication and restricted repetitive behaviors and interests. There are no FDA-approved medications for these core symptoms, and there are limited data regarding pharmacological management of ASD in adults. Here, the literature was reviewed in an effort to develop an algorithm for pharmacological management of core symptoms of ASD in adults. The literature search was conducted using PubMed. It was very difficult to distil a plausible algorithm from these data. Not included in this review are behavioral strategies, which are first-line. For instances when medication is being considered for management of core ASD symptoms in adults, the authors suggest starting with fluvoxamine as first-line, with possible consideration of a second SSRI trial if there is an inadequate or no response to fluvoxamine. The next step, if there is comorbid irritability, is to consider a second-generation antipsychotic. If there is no comorbid irritability, in the final step of the tentative algorithm, there are possible augmenting agents: propranolol, memantine, d-cycloserine, and oxytocin. Management of the symptoms of ASD requires a comprehensive treatment approach, and treatment planning must be individualized. Treatment of core ASD symptoms is not always desired. Further studies are needed to develop a stronger evidence base to support pharmacological management of core symptoms.

The Psychopharmacology Algorithm Project at the Harvard South Shore Program: An update on bipolar depression.

BACKGROUND: The Psychopharmacology Algorithm Project at the Harvard South Shore Program (PAPHSS) published algorithms for bipolar depression in 1999 and 2010. Developments over the past 9 years suggest that another update is needed. METHODS: The 2010 algorithm and associated references were reevaluated. A literature search was conducted on PubMed for recent studies and review articles to see what changes in the recommendations were justified. Exceptions to the main algorithm for special patient populations, including those with attention-deficit hyperactivity disorder (ADHD), posttraumatic stress disorder (PTSD), substance use disorders, anxiety disorders, and women of childbearing potential, and those with common medical comorbidities were considered. RESULTS: Electroconvulsive therapy (ECT) is still the first-line option for patients in need of urgent treatment. Five medications are recommended for early usage in acute bipolar depression, singly or in combinations when monotherapy fails, the order to be determined by considerations such as side effect vulnerability and patient preference. The five are lamotrigine, lurasidone, lithium, quetiapine, and cariprazine. After trials of these, possible options include antidepressants (bupropion and selective serotonin reuptake inhibitors are preferred) or valproate (very small evidence-base). In bipolar II depression, the support for antidepressants is a little stronger but depression with mixed features and rapid cycling would usually lead to further postponement of antidepressants. Olanzapine+fluoxetine, though Food and Drug Administration (FDA) approved for bipolar depression, is not considered until beyond this point, due to metabolic side effects. The algorithm concludes with a table of other possible treatments that have some evidence. CONCLUSIONS: This revision incorporates the latest FDA-approved treatments (lurasidone and cariprazine) and important new studies and organizes the evidence systematically.

The psychopharmacology algorithm project at the Harvard South Shore Program: An algorithm for adults with obsessive-compulsive disorder.

A previous algorithm for the pharmacological treatment of obsessive-compulsive disorder was published in 2012. Developments over the past 7 years suggest an update is needed. The authors conducted searches in PubMed, focusing on new studies and reviews since 2012 that would support or change previous recommendations. We identified exceptions to the main algorithm, including pregnant women and women of child-bearing potential, the elderly, and patients with common medical and psychiatric co-morbidities. Selective serotonin reuptake inhibitors (SSRIs) are still first-line. An adequate trial requires a period at typical antidepressant doses and dose adjustments guided by a plasma level to evaluate for poor adherence or ultra-rapid metabolism. If the response is inadequate, consider a trial of another SSRI this time possibly taken to a very high dose. Clomipramine could be an alternative. If the response to the second trial remains inadequate, the next recommendation is to augment with aripiprazole or risperidone. Alternatively, augmentation with novel agents could be selected, including glutamatergic (memantine, riluzole, topiramate, n-acetylcysteine, lamotrigine), serotonergic (ondansetron), and anti-inflammatory (minocycline, celecoxib) agents. A third option could be transcranial magnetic stimulation. Lastly, after several of these trials, deep brain stimulation and cingulotomy have evidence for a role in the most treatment-refractory patients.

Prevalence and clinical features of atypical depression among patients with major depressive disorder in China.

BACKGROUND: Little is known about the demographic and clinical features of the atypical subtype of major depressive disorder (MDD) patients in China. This study set out to investigate the prevalence of atypical depression in MDD patients in China, and identify its demographic and clinical features. METHODS: The study was conducted in 13 major psychiatric hospitals or in the psychiatric units of general hospitals in China, and recruited a sample of 1172 patients diagnosed with MDD. The patients' demographic and clinical features and prescriptions of psychotropic drugs were collected using a standardized questionnaire designed for the study. RESULTS: The prevalence of atypical depression was 15.3%. In multiple logistic regression analyses, compared to the non-atypical depression patients, the atypical depression patients were more likely to have depressive episodes with suicide ideation and attempts (OR = 1.49, 95% CI = 1.06, 2.10, P = 0.023), depressive episodes with psychotic features (OR = 2.15, 95% CI = 1.43, 3.22, P < 0.001), seasonal depressive episodes (OR = 1.77, 95% CI = 1.12, 2.78, P = 0.014), an earlier age of onset (OR = 0.98, 95% CI = 0.96, 0.99, P = 0.001), and lifetime depressive episodes (OR = 1.07, 95% CI = 1.01, 1.13, P = 0.020). LIMITATIONS: The assessment of atypical features was not based on a validated rating scale. CONCLUSION: Our results indicate that atypical depression is common in Chinese patients with MDD. MDD with atypical features may be more severe and debilitating than patients with non-atypical features.

Implementing and Sustaining Team-Based Telecare for Bipolar Disorder: Lessons Learned from a Model-Guided, Mixed Methods Analysis.

BACKGROUND: Telemental health interventions have empirical support from clinical trials and structured demonstration projects. However, their implementation and sustainability under less structured clinical conditions are not well demonstrated. INTRODUCTION: We conducted a follow-up analysis of the implementation and sustainability of a clinical video teleconference-based collaborative care model for individuals with bipolar disorder treated in the Department of Veterans Affairs to (a) characterize the extent of implementation and sustainability of the program after its establishment and (b) identify barriers and facilitators to implementation and sustainability. MATERIALS AND METHODS: We conducted a mixed methods program evaluation, assessing quantitative aspects of implementation according to the Reach, Efficacy, Adoption, Implementation, and Maintenance implementation framework. We conducted qualitative analysis of semistructured interviews with 16 of the providers who submitted consults, utilizing the Integrated Promoting Action on Research Implementation in the Health Services implementation framework. RESULTS: The program demonstrated linear growth in sites (n = 35) and consults (n = 915) from late 2011 through mid-2016. Site-based analysis indicated statistically significant sustainability beyond the first year of operation. Qualitative analysis identified key facilitators, including consult content, ease of use via electronic health record, and national infrastructure. Barriers included availability of telehealth space, equipment, and staff at the sites, as well as the labor-intensive nature of scheduling. DISCUSSION: The program achieved continuous growth over almost 5 years due to (1) successfully filling a need perceived by providers, (2) developing in a supportive context, and (3) receiving effective facilitation by national and local infrastructure. CONCLUSION: Clinical video teleconference-based interventions, even multicomponent collaborative care interventions for individuals with complex mental health conditions, can grow vigorously under appropriate conditions.

The Psychopharmacology Algorithm Project at the Harvard South Shore Program: An Algorithm for Generalized Anxiety Disorder.

This revision of previous algorithms for the pharmacotherapy of generalized anxiety disorder was developed by the Psychopharmacology Algorithm Project at the Harvard South Shore Program. Algorithms from 1999 and 2010 and associated references were reevaluated. Newer studies and reviews published from 2008-14 were obtained from PubMed and analyzed with a focus on their potential to justify changes in the recommendations. Exceptions to the main algorithm for special patient populations, such as women of childbearing potential, pregnant women, the elderly, and those with common medical and psychiatric comorbidities, were considered. Selective serotonin reuptake inhibitors (SSRIs) are still the basic first-line medication. Early alternatives include duloxetine, buspirone, hydroxyzine, pregabalin, or bupropion, in that order. If response is inadequate, then the second recommendation is to try a different SSRI. Additional alternatives now include benzodiazepines, venlafaxine, kava, and agomelatine. If the response to the second SSRI is unsatisfactory, then the recommendation is to try a serotonin-norepinephrine reuptake inhibitor (SNRI). Other alternatives to SSRIs and SNRIs for treatment-resistant or treatment-intolerant patients include tricyclic antidepressants, second-generation antipsychotics, and valproate. This revision of the GAD algorithm responds to issues raised by new treatments under development (such as pregabalin) and organizes the evidence systematically for practical clinical application.

Team-Based Telecare for Bipolar Disorder.

INTRODUCTION: Numerous randomized controlled trials indicate that collaborative chronic care models improve outcome in a wide variety of mental health conditions, including bipolar disorder. However, their spread into clinical practice is limited by the need for a critical mass of patients and specialty providers in the same locale. Clinical videoconferencing has the potential to overcome these geographic limitations. MATERIALS AND METHODS: A videoconference-based collaborative care program for bipolar disorder was implemented in the Department of Veterans Affairs. Program evaluation assessed experience with the first 400 participants, guided by five domains specified by the American Telemedicine Association: treatment engagement, including identification of subpopulations at risk for not being reached; participation in treatment; clinical impact; patient safety; and quality of care. RESULTS: Participation rates resembled those for facility-based collaborative care. No participant characteristics predicted nonengagement. Program completers demonstrated significant improvements in several clinical indices, without evidence of compromise in patient safety. Guideline-based quality of care assessment after 1 year indicated increased lithium use, decreased antidepressant use, and increased prazosin use in individuals with comorbid post-traumatic stress disorder, but no impact on already high rates of lithium serum level monitoring. DISCUSSION: Clinical videoconferencing can extend the reach of collaborative care models for bipolar disorder. The next step involves assessment of the videoconference-based collaborative care for other serious mental health conditions, investigation of barriers and facilitators of broad implementation of the model, and evaluation of the business case for deployment and sustainability in clinical practice.

The Ascendancy of Second-Generation Antipsychotics as Frontline Antimanic Agents.

INTRODUCTION: Knowledge of the factors affecting the adoption of new medications can enhance mental health care and guide quality improvement and policy development. Food and Drug Administration indications for treating bipolar disorder with several second-generation antipsychotics (SGAs) in the 2000s represent an opportunity to identify factors that impact the spread of a then-innovative treatment through a new population. METHODS: Analysis of Department of Veterans Affairs administrative data identified the population of 170,811 veterans diagnosed with bipolar disorder from 2003 to 2010. We analyzed time trends and predictors of antimanic choice (SGA vs other) among the 40,512 outpatients with bipolar disorder who initiated their first VA outpatient antimanic prescription, using multinomial logistic regression in month-by-month analyses. We conducted classwise analyses and investigated prespecified predictors among specific agents. RESULTS: In classwise analyses, SGAs supplanted lithium, valproate, and carbamazepine/oxcarbazepine as the most commonly initiated antimanics by 2007. Psychosis, but not other indices of severity, predicted SGA initiation. Demographic analyses did not identify substantial disparities in initiation of SGAs. Drug-specific analyses revealed some consideration of medical comorbidities in choosing among specific antimanic agents, although effect sizes were small. Most patients initiating an antimanic had received an antidepressant in the previous year. DISCUSSION: Second-generation antipsychotics quickly became the frontline antimanic treatment for bipolar disorder, although antidepressants most commonly predated antimanic prescriptions. Second-generation antipsychotics were used for a broad range of patients rather than being restricted to a severely ill subpopulation. The modest association of antimanic choice with relevant medical comorbidities suggests that continued attention to quality prescribing practices is warranted.

Patterns of initiation of second generation antipsychotics for bipolar disorder: a month-by-month analysis of provider behavior.

BACKGROUND: Several second generation antipsychotics (SGAs) received FDA approval for bipolar disorder in the 2000s. Although efficacious, they have been costly and may cause significant side effects. Little is known about the factors associated with prescribers' decisions to initiate SGA prescriptions for this condition. METHODS: We gathered administrative data from the Department of Veterans Affairs on 170,713 patients with bipolar disorder between fiscal years 2003-2010. Patients without a prior history of taking SGAs were considered eligible for SGA initiation during the study (n =126,556). Generalized estimating equations identified demographic, clinical, and comorbidity variables associated with initiation of an SGA prescription on a month-by-month basis. RESULTS: While the number of patients with bipolar disorder using SGAs nearly doubled between 2003 and 2010, analyses controlling for patient characteristics and the rise in the bipolar population revealed a 1.2% annual decline in SGA initiation during this period. Most medical comorbidities were only modestly associated with overall SGA initiation, although significant differences emerged among individual SGAs. Several markers of patient severity predicted SGA initiation, including previous hospitalizations, psychotic features, and a history of other antimanic prescriptions; these severity markers became less firmly linked to SGA initiation over time. Providers in the South were somewhat more likely to initiate SGA treatment. CONCLUSIONS: The number of veterans with bipolar disorder prescribed SGAs is rising steadily, but this increase appears primarily driven by a corresponding increase in the bipolar population. Month-by-month analyses revealed that higher illness severity predicted SGA initiation, but that this association may be weakening over time.

The psychopharmacology algorithm project at the Harvard South Shore Program: an algorithm for acute mania.

This new algorithm for the pharmacotherapy of acute mania was developed by the Psychopharmacology Algorithm Project at the Harvard South Shore Program. The authors conducted a literature search in PubMed and reviewed key studies, other algorithms and guidelines, and their references. Treatments were prioritized considering three main considerations: (1) effectiveness in treating the current episode, (2) preventing potential relapses to depression, and (3) minimizing side effects over the short and long term. The algorithm presupposes that clinicians have made an accurate diagnosis, decided how to manage contributing medical causes (including substance misuse), discontinued antidepressants, and considered the patient's childbearing potential. We propose different algorithms for mixed and nonmixed mania. Patients with mixed mania may be treated first with a second-generation antipsychotic, of which the first choice is quetiapine because of its greater efficacy for depressive symptoms and episodes in bipolar disorder. Valproate and then either lithium or carbamazepine may be added. For nonmixed mania, lithium is the first-line recommendation. A second-generation antipsychotic can be added. Again, quetiapine is favored, but if quetiapine is unacceptable, risperidone is the next choice. Olanzapine is not considered a first-line treatment due to its long-term side effects, but it could be second-line. If the patient, whether mixed or nonmixed, is still refractory to the above medications, then depending on what has already been tried, consider carbamazepine, haloperidol, olanzapine, risperidone, and valproate first tier; aripiprazole, asenapine, and ziprasidone second tier; and clozapine third tier (because of its weaker evidence base and greater side effects). Electroconvulsive therapy may be considered at any point in the algorithm if the patient has a history of positive response or is intolerant of medications.

The psychopharmacology algorithm project at the Harvard South Shore Program: an update on schizophrenia.

This article is an update of the algorithm for schizophrenia from the Psychopharmacology Algorithm Project at the Harvard South Shore Program. A literature review was conducted focusing on new data since the last published version (1999-2001). The first-line treatment recommendation for new-onset schizophrenia is with amisulpride, aripiprazole, risperidone, or ziprasidone for four to six weeks. In some settings the trial could be shorter, considering that evidence of clear improvement with antipsychotics usually occurs within the first two weeks. If the trial of the first antipsychotic cannot be completed due to intolerance, try another until one of the four is tolerated and given an adequate trial. There should be evidence of bioavailability. If the response to this adequate trial is unsatisfactory, try a second monotherapy. If the response to this second adequate trial is also unsatisfactory, and if at least one of the first two trials was with risperidone, olanzapine, or a first-generation (typical) antipsychotic, then clozapine is recommended for the third trial. If neither trial was with any these three options, a third trial prior to clozapine should occur, using one of those three. If the response to monotherapy with clozapine (with dose adjusted by using plasma levels) is unsatisfactory, consider adding risperidone, lamotrigine, or ECT. Beyond that point, there is little solid evidence to support further psychopharmacological treatment choices, though we do review possible options.

The Psychopharmacology Algorithm Project at the Harvard South Shore Program: an update on posttraumatic stress disorder.

BACKGROUND: This project aimed to provide an organized, sequential, and evidence-supported approach to the pharmacotherapy of posttraumatic stress disorder (PTSD), following the format of previous efforts of the Psychopharmacology Algorithm Project at the Harvard South Shore Program. METHOD: A comprehensive literature review was conducted to determine the best pharmacological choices for PTSD patients and to update the last published version (1999) of the algorithm. We focused on optimal pharmacological interventions to address the prominent symptoms of PTSD, with additional attention to the impact that common comorbidities have on treatment choices. RESULTS: We found that SSRIs and SNRIs are not as effective as previously thought, and that awareness of their long-term side effects has increased. New evidence suggests that addressing fragmented sleep and nightmares can improve symptoms (in addition to insomnia) that are frequently seen with PTSD (e.g., hyperarousal, reexperiencing). Prazosin and trazodone are emphasized at this initial step; if significant PTSD symptoms remain, an antidepressant may be tried. For PTSD-related psychosis, an antipsychotic may be added. In resistant cases, two or three antidepressants may be used in sequence. Following that, or with partial improvement and residual symptomatology, augmentation may be tried; the best options are antipsychotics, clonidine, topiramate, and lamotrigine. CONCLUSION: This heuristic may be helpful in producing faster symptom resolution, fewer side effects, and increased compliance.

The psychopharmacology algorithm project at the Harvard South Shore Program: an update on bipolar depression.

This updated version of the bipolar depression algorithm of the Psychopharmacology Algorithm Project at the Harvard South Shore Program aims to provide an organized, sequential, and evidence-supported approach for the treatment of that disorder. After initial evaluation and diagnosis, the psychiatrist should first assess whether there is an urgent indication for ECT. If ECT is not indicated, and the patient has psychotic symptoms, then an antipsychotic should be part of the medication regimen. Next, if the patient is not currently treated with mood stabilizers, there is a slight preference for lithium. If lithium is not effective or tolerated, treatment with quetiapine or lamotrigine should be initiated. If the patient is currently taking other mood stabilizers, their dosage should be optimized, and the clinician should consider adding or switching to lithium, quetiapine, or lamotrigine. Next, if the patient is not at especially high risk of mood destabilization, an antidepressant can be added in the bipolar depressed patient who has failed trials of lithium, quetiapine, and lamotrigine. Rapid-cycling depressed patients may require combinations of two or three mood stabilizers. ECT, along with other psychopharmacological options, could be reconsidered for the treatment of refractory bipolar depressed patients.

The Psychopharmacology Algorithm Project at the Harvard South Shore Program: an update on psychotic depression.

This new version of the psychotic depression algorithm has been developed by the Psychopharmacology Algorithm Project at the Harvard South Shore Program. The most effective treatment modality for inpatients with severe psychotic depression is electroconvulsive therapy. The first-line psychopharmacological treatment is a combination of an antidepressant (either a tricyclic or a selective serotonin reuptake inhibitor) and an antipsychotic. If one of these combinations has failed, consider switching to the other. If both combinations have failed, the next psychopharmacological option would be to augment the combination with lithium. Another option, though with limited evidence, is monotherapy with clozapine. If there is a good reason to avoid combination therapy with an antipsychotic, then a trial of monotherapy with a TCA or an SSRI can be supported. If that fails, adding an antipsychotic or ECT should be considered.

Rationale for emphasis on management over treatment of schizophrenia in clinical practice.

There is a need for clinicians to emphasize "management" over "treatment" in their pharmacologic approach to schizophrenia. Using the term "treatment" may set up unrealistic expectations for a fuller recovery to a premorbid level of functioning, with potential use of overmedication and polypharmacy as well as possible unwanted adverse effects. The "management" concept allows clinicians to work with the best current medication practice, taking into account the wide variability in the course of illness and response to treatment. Prescribing clinicians should work collaboratively with other caregivers to enhance adaptive behavior and functional outcome through psychosocial rehabilitative interventions, within the context of recovery.