Time-limited Treatment Research Articles

Combination therapy for ischemic stroke: Novel approaches to lengthen therapeutic window of tissue plasminogen activator

Tissue plasminogen activator (tPA) thrombolysis continues to be the gold standard therapy for ischemic stroke. Due to the time-limited treatment window, within 4.5 h of stroke onset, and a variety of potentially deadly complications related to delayed administration, particularly hemorrhagic transformation (HT), clinical use of tPA is limited. Combination therapies with other interventions, drug or nondrug, have been hypothesized as a logical approach to enhancing tPA effectiveness. Here, we discuss various potential pharmacological and nondrug treatments to minimize adverse effects, primarily HT, associated with delayed tPA administration. Pharmacological interventions include many that support the integrity of the blood–brain barrier (i.e., atorvastatin, batimastat, candesartan, cilostazol, fasudil, and minocycline), promote vascularization and preserve cerebrovasculature (i.e., coumarin derivative IMM-H004 and granulocyte-colony stimulating factor), employing other mechanisms of action (i.e., oxygen transporters and ascorbic acid). Nondrug treatments are comprised of stem cell transplantation and gas therapies with multi-faceted approaches. Combination therapy with tPA and the aforementioned treatments demonstrated promise for mitigating the adverse complications associated with delayed tPA treatment and rescuing stroke-induced behavioral deficits. Therefore, the conjunctive therapy method is a novel therapeutic approach that can attempt to minimize the limitations of tPA treatment and possibly increase the therapeutic window for ischemic stroke treatment.

Using best interests meetings for people in a prolonged disorder of consciousness to improve clinical and ethical management

Current management of people with prolonged disorders of consciousness is failing patients, families and society. The causes include a general lack of concern, knowledge and expertise; a legal and professional...

Narrative review of provider behavior in primary care behavioral health: How process data can inform quality improvement.

Primary care behavioral health (PCBH) is a population-based approach to delivering mental and behavioral health care in the primary care setting. Implementation of the PCBH model varies across practice settings, which can impact how PCBH providers deliver services to patients and in turn may predict a variety of important outcomes. This article aims to characterize PCBH provider engagement in key processes of integrated care as demonstrated in results from empirical studies of real-world clinical practice. For this narrative review of published studies on PCBH provider engagement in processes of care, PubMed and PsycINFO databases were searched from January 1990 through May 2016 to identify relevant articles. Provider adherence to the brief, time-limited treatment model appears suboptimal. Common mental health conditions, such as depression, were often the primary focus of provider attention, with less consistent emphasis on behavioral medicine concerns. Whereas providers regularly conducted qualitative functional assessments with patients, routine use of standardized measures was low. Engagement in interprofessional collaboration with the primary care team was also low, but engagement in behaviors that fostered therapeutic relationships was high. This review identified several strengths and weaknesses of typical PCBH provider practices. Results are discussed in relation to their value as areas for future quality improvement initiatives that can improve PCBH service delivery and, ultimately, patient outcomes. (PsycINFO Database Record

Use or Abuse? A Qualitative Study of Emergency Physicians' Views on Use of Observation Stays at Three Hospitals in the United States and England

Accumulating evidence has shown increasing use of observation stays for patients presenting to emergency departments and requiring diagnostic evaluation or time-limited treatment plans, but critics suggest that this expansion arises from hospitals' concerns to maximize revenue and shifts costs to patients. Perspectives of physicians making decisions to admit, observe, or discharge have been absent from the debate. We examine the views of emergency physicians in the United States and England on observation stays, and what influences their decisions to use observation services. We undertook in-depth, qualitative interviews with a purposive sample of physicians in 3 hospitals across the 2 countries and analyzed these using an approach based on the constant-comparison method. Limitations include the number of sites, whose characteristics are not generalizable to all institutions, and the reliance on self-reported interview accounts. Physicians used observation status for the specific presentations for which it is well evidenced but acknowledged administrative and financial considerations in their decisionmaking. They also highlighted an important role for observation not described in the literature: as a "safe space," relatively immune from the administrative gaze, where diagnostic uncertainties, sociomedical problems, and medicolegal challenges could be contained. Observation status increases the options available to admitting physicians in a way that they valued for its potential benefits to patient safety and quality of care, but some of these have been neglected in the literature to date. Reform to observation status should address these important but previously unacknowledged functions.

Psychologists' Perspectives on Therapy Termination and the Use of Therapy Engagement/Retention Strategies.

Therapists tend to underestimate the number of clients who make unilateral decisions to end treatment in their own practices. Therapists are unlikely to take steps to engage and retain clients in treatment unless they believe that unilateral termination is a significant problem. Clients who unilaterally end treatment are often experiencing problems with the process of therapy (e.g., dissatisfaction, lack of fit, feeling as though therapy is going nowhere), whereas therapists often attribute failed therapy to clients. It is important to be aware of this tendency and look for other explanations. It is worthwhile to actively solicit clients' barriers in an effort to mitigate them. The empirical literature provides ample evidence that it is helpful for therapists to deliberately employ strategies to engage and retain clients in therapy. All therapists would benefit from considering which strategies fit with their practices. Although almost all therapists emphasize building the early working alliance, and this is essential to good outcome, other evidence-based methods of engaging clients in therapy are largely underutilized, such as systematically monitoring client progress and barriers, placing time limits on treatment, using appointment reminders, and case management.

In memoriam: Dr. Andrew Czeizel.

In memoriam: Dr. Andrew Czeizel.

Abstract B23: Epigenetic control of prostate epithelial stem cell differentiation

Abstract Introduction: Hormone manipulation offers an effective but short term and time-limited treatment for human prostate cancers, reducing both tumor bulk and serum levels of prostate-specific antigen. In normal prostate, castration results in a loss of luminal cells and persistence of a poorly differentiated basal-like population, which is responsible for repopulation after restoration of hormone levels. However in fetal prostate development, the hormonal stimulus is provided indirectly to the developing epithelial structures via androgen-sensitive stromal cells. To study the drivers of prostate epithelial cell differentiation, we sought the epigenetic factors affecting cell fate in adult human normal, hyperplastic and malignant epithelium, to provide more precise targets for prostate cancer therapy, based on this developmental paradigm. Methods: We have adopted a multiple model approach for the study of human prostate stem cells. Epithelial cell fractions are prepared from human tissues using multiparametric FACS with a Beckman Coulter Astrios, or adhesion-based separations from (i) MRI guided biopsies of prostate tissues (and patient matched non- tumor tissues) (ii) primary cultures in defined serum free medium from prostate tissues depleted of stromal cells and (iii) a novel set of near patient mouse xenografts of human tissues. In these systems the (normal) colony forming and (malignant) tumor-inducing capacity largely resides in a CD133+/ CD44+/a2B1 integrin Hi/CD49f population which comprises 1% and <0.1% of the normal and malignant epithelium respectively. Cell populations were analyzed independently for their gene expression patterns, non-coding RNA expression, histone modifications and genome CpG methylation. Using a modified analysis algorithm we then related gene expression to both miRNA expression and genomic methylation/ chromatin condensation. Results: At the chromosomal level, prostate SC display a unique pattern of CpG methylation compared to their more differentiated progeny, with distinct changes in cancer. The SC also have a characteristic bivalent chromatin pattern when probed for specific histone modifications. This bivalent chromatin pattern is also indicative, in embryonic systems, of monoallelic gene expression, which was confirmed in prostate SC populations by analysis of the prostate-specific TMPRSS2 gene, in both native and fused form (to ERG). MicroRNA expression patterns are tightly linked to SC differentiation, rather than carcinogenesis, and the miRNAs expressed in prostate SC most closely resemble those in human embryonic SC, and intriguingly in the most malignant forms of prostate cancer. Since miRNAs can control expression of multiple genes, we have devised an algorithm to predict regulation of only those genes expressed in the prostate epithelium. Perhaps significantly for cancer treatment, the principal functions controlled by miRNA expression are both DNA damage repair and wnt signaling, manipulation of which can increase the radiation resistance resident in the SC population. By studying genes which are tightly co-regulated during cell differentiation, we defined 4 non-overlapping sets of genes in which retinoic acid acts as a driver of primitive cell differentiation, an intermediate cell type expressing genes with a bivalent response to RA and androgens, and committed basal/luminal cells in which androgen control of cell fate dominates. Discussion: By studying highly enriched cell populations in different model systems, all of which are derived from primary human tissues, we have built up a complex picture of epigenetic regulation of gene expression during differentiation of human prostate. Many of these essential functions are related to similar functions in developing prostate tissue, but are often characterized by phenotypic plasticity, where the differentiated products of asymmetric division (self-renewal) can revert to a stem-like state. Citation Format: Norman James Maitland, John Packer. Epigenetic control of prostate epithelial stem cell differentiation. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr B23.

Investigation of abbreviated 4 and 8 item versions of the PTSD Checklist 5

Posttraumatic stress disorder (PTSD) is a significant public health concern associated with marked impairment across the lifespan. Exposure to traumatic events alone, however, is insufficient to determine if an individual has PTSD. PTSD is a heterogeneous diagnosis such that assessment of all 20 symptoms is problematic in time-limited treatment settings. Brief assessment tools that identify those at risk for PTSD and measure symptom severity are needed to improve access to care and assess treatment response. The present study evaluated abbreviated measures of PTSD symptoms derived from the PTSD Checklist for DSM-5 (PCL-5) – a 20-item validated measure of PTSD symptoms – across two studies. In the first, using a community sample of adults exposed to a traumatic event, 4-and 8-item versions of the PCL-5 were identified that were highly correlated with the full PCL-5. In the second, using a sample of combat veterans, the 4-and 8-item measures had comparable diagnostic utility to the total-scale PCL-5. These results provide support for an abbreviated measure of the PCL-5 as an alternative to the 20-item total scale.

Ultra-Low-Dose Buprenorphine as a Time-Limited Treatment for Severe Suicidal Ideation: A Randomized Controlled Trial.

Suicidal ideation and behavior currently have no quick-acting pharmacological treatments that are suitable for independent outpatient use. Suicidality is linked to mental pain, which is modulated by the separation distress system through endogenous opioids. The authors tested the efficacy and safety of very low dosages of sublingual buprenorphine as a time-limited treatment for severe suicidal ideation. This was a multisite randomized double-blind placebo-controlled trial of ultra-low-dose sublingual buprenorphine as an adjunctive treatment. Severely suicidal patients without substance abuse were randomly assigned to receive either buprenorphine or placebo (in a 2:1 ratio), in addition to their ongoing individual treatments. The primary outcome measure was change in suicidal ideation, as assessed by the Beck Suicide Ideation Scale at the end of each of 4 weeks of treatment. Patients who received ultra-low-dose buprenorphine (initial dosage, 0.1 mg once or twice daily; mean final dosage=0.44 mg/day; N=40) had a greater reduction in Beck Suicide Ideation Scale scores than patients who received placebo (N=22), both after 2 weeks (mean difference -4.3, 95% CI=-8.5, -0.2) and after 4 weeks (mean difference=-7.1, 95% CI=-12.0, -2.3). Concurrent use of antidepressants and a diagnosis of borderline personality disorder did not affect the response to buprenorphine. No withdrawal symptoms were reported after treatment discontinuation at the end of the trial. The time-limited, short-term use of very low dosages of sublingual buprenorphine was associated with decreased suicidal ideation in severely suicidal patients without substance abuse. Further research is needed to establish the efficacy, safety, dosing, and appropriate patient populations for this experimental treatment.

The development of an evidence-based treatment: Regulation-Focused Psychotherapy for Children with externalising behaviours (RFP-C)

There is a critical need for the development, evaluation and implementation of evidence-based psychodynamic treatments for children and adolescents. Currently, there are no empirically supported, manualised psychodynamic treatments for children and adolescents with disruptive behaviour problems. The field of manualised psychodynamic treatments with measurable equivalence or superiority to other established forms of psychotherapy is in its nascent stage. This paper details a novel, manualised, time-limited psychodynamic treatment approach for children who manifest disruptive behaviours and emotional dysregulation. Regulation-Focused Psychotherapy for Children (RFP-C) conceptualises children’s disruptive and acting out behaviours as expressions of maladaptive emotion regulation. Externalising symptoms are conceptualised as attempts to defend against painful emotions and thus protect the child from disturbing feelings such as sadness, shame and guilt. This paper provides the theoretical basis for the treatment approach and through the use of a clinical example demonstrates the systematic application of RFP-C in a single case.

Mania.

Primary mania and hypomania in full or subsyndromal forms are the defining features of bipolar disorder and are common in neurologic patients, as are manic syndromes precipitated by medications used to treat neurologic disorders. This article addresses the diagnosis, pathophysiology, treatment, and course of bipolar disorder after a manic episode as well as mania as a manifestation of neurologic disease. Mania can be a primary psychiatric disorder but can also be a symptom of a neurologic disorder, especially right-sided cerebrovascular disease. Treatments (such as corticosteroids and dopaminergic agents) for neurologic illnesses regularly induce mania. The neurobiology of primary mania and bipolar disorder involves alterations in intracellular signaling, changes in gene expression, neural network interactions, and apoptosis. Except when induced by time-limited treatment with a provoking agent, mania tends to be highly recurrent and to alternate or be exhibited alongside depression. Symptoms of mania become more complex and treatment refractory with time, although effective treatment improves the long-term outcome. Behavioral manifestations of mania may be more obvious than affective symptoms, especially in patients with aprosodia. Atypical antipsychotic drugs are often first-line acute treatments, but the evidence supporting their long-term prophylactic efficacy is questionable. In addition to being an established mood stabilizer, lithium has putative neuroprotective properties, although a side effect can be impaired memory.

Development of a group and family‐based cognitive behavioural therapy program for youth at risk for psychosis

The onset of psychosis typically occurs during adolescence or early adulthood and can have a detrimental impact on social and cognitive development. Cognitive behavioural therapy (CBT) shows promise in reducing the risk of psychosis. Teaching families to apply CBT with their offspring may bolster therapeutic gains made in time-limited treatment. We developed a comprehensive group-and-family-based CBT (GF-CBT) program that aims to facilitate psychosocial recovery, decrease symptoms and prevent transition to psychosis in youth at risk. GF-CBT is grounded in ecological systems and cognitive theories, resilience models and research on information processing in delusions. The theoretical rationale and description of GF-CBT are presented together with a pilot study that evaluated the program's feasibility and explored participants' outcomes. Youth ages 16-21 at risk for psychosis and their families participated in an open trial with pre, post and 3-month follow-up assessments conducted by an independent evaluator. The Comprehensive Assessment of At-Risk Mental States was the primary clinical outcome measure. All enrolled participants (n = 6) completed GF-CBT and all remitted from at-risk mental state (ARMS). As a group participants showed statistically significant decreases in attenuated psychotic symptoms, negative symptoms, depression, cognitive biases and improvements in functioning. Family members showed significant improvements in use of CBT skills, enhanced communication with their offspring, and greater confidence in their ability to help. Gains were maintained at follow-up. GF-CBT may delay or prevent transition to psychosis in youth at risk, and potentially facilitate recovery from ARMS. More rigorous, controlled research is needed to further evaluate this program.

The elephant tied up with string: a clinical case study showing the importance of NHS provision of intensive, time-limited psychoanalytic psychotherapy treatments

Prof. Richard Layard's influential advocacy for greater provision of ‘evidence-based’ psychological therapies, based in part on an economic rationale, has lead to greatly increased provision of cognitive behavioural therapy (CBT) and short-term therapies for depression, through the Increasing Access to Psychological Therapies (IAPT) initiative, whilst longer-term psychodynamic treatments are under threat, criticised as lacking an evidence base. This paper argues for the continuing provision of intensive thrice-weekly psychoanalytic psychotherapy treatments, time-limited to two years. It does so by describing such a treatment within an NHS psychotherapy department with a patient with a long history of severe personality pathology, including significant levels of perversity. The paper describes the patient's difficulties and his movement through the treatment, focussing on his difficulties making genuine emotional contact, his destructiveness of such contact, his acting out in the treatment, his perversity and the vital working through of the ending. The shifts the patient made are described, and follow-up information on the patient is given. The paper discusses the unique benefits of time-limited treatment and intensive psychoanalytic treatments for this ‘hard-to-help’ group of patients, and the economic rationale that can be made for such treatments.

S.18.01 Low-dose and time-limited antipsychotic treatment strategies in schizophrenia

S.18.01 Low-dose and time-limited antipsychotic treatment strategies in schizophrenia

The Efficacy of Cognitive-Behavioral Therapy and Psychodynamic Therapy in the Outpatient Treatment of Major Depression: A Randomized Clinical Trial

Objective The efficacy of psychodynamic therapies for depression remains open to debate because of a paucity of high-quality studies. The authors compared the efficacy of psychodynamic therapy with that of cognitive-behavioral therapy (CBT), hypothesizing nonsignificant differences and the noninferiority of psychodynamic therapy relative to CBT. Method A total of 341 adults who met DSM-IV criteria for a major depressive episode and had Hamilton Depression Rating Scale (HAM-D) scores ≥14 were randomly assigned to 16 sessions of individual manualized CBT or short-term psychodynamic supportive therapy. Severely depressed patients (HAM-D score >24) also received antidepressant medication according to protocol. The primary outcome measure was posttreatment remission rate (HAM-D score ≤7). Secondary outcome measures included mean posttreatment HAM-D score and patient-rated depression score and 1-year follow-up outcomes. Data were analyzed with generalized estimating equations and mixed-model analyses using intent-to-treat samples. Noninferiority margins were prespecified as an odds ratio of 0.49 for remission rates and a Cohen’s d value of 0.30 for continuous outcome measures. Results No statistically significant treatment differences were found for any of the outcome measures. The average posttreatment remission rate was 22.7%. Noninferiority was shown for posttreatment HAM-D and patient-rated depression scores but could not be demonstrated for posttreatment remission rates or any of the follow-up measures. Conclusions The findings extend the evidence base of psychodynamic therapy for depression but also indicate that time-limited treatment is insufficient for a substantial number of patients encountered in psychiatric outpatient clinics. (Reprinted with permission from the American Journal of Psychiatry 2013; 170:1041–1050)

Effectiveness of Group-Delivered Cognitive Therapy and Treatment Length in Women Veterans with PTSD.

The effectiveness and length of group-delivered cognitive treatment for Posttraumatic Stress Disorder (PTSD) was examined in a sample of women veterans. The sample included 271 primarily non-Hispanic white (61%) and Hispanic (25%) women veterans treated in 8-, 10-, or 12-group length sessions with manualized cognitive therapy for PTSD. Outcome was measured with the PTSD Symptom Checklist (PCL) in an intention-to-treat analysis (N = 271), in completer subjects (n = 172), and with group as the unit of analysis (n = 47 groups). Significant decreases in PTSD were found in the full sample (effect size [ES] range = 0.27 to 0.38), completers (ES range = 0.37 to 0.54), and group as the unit of analysis (ES range = 0.71 to 0.92), suggesting effectiveness of cognitive group treatment for PTSD. PCL scores significantly improved in the 8, 10, and 12 group lengths, with no differences between each. Clinical improvement showed a third decreasing 10 or more PCL points and 22% no longer meeting PTSD diagnostic criteria, with the best results in the 10-session group. The results suggest group-delivered cognitive therapy is an effective, efficient, time-limited treatment for PTSD.

Real relationship, working alliance, transference/countertransference and outcome in time-limited counseling and psychotherapy

Six client/therapist dyads (three therapists each working with two clients) were studied to determine how the real relationship unfolds over the course of time-limited treatment and how this unfolding relates to the development of the client/therapist working alliance, client transference, and therapist countertransference. We also examined how these indices of the relationship fluctuate as a function of treatment outcome. Results indicate that in general for all six dyads, therapists’ and clients’ ratings of the real relationship and working alliance were strong throughout treatment. However, patterns of real relationship and working alliance over the course of treatment varied between dyads categorized as more vs. less successful. Therapists’ countertransference was low, as was client transference, but differences in ratings were evident when the dyads were classified by outcome.

The Efficacy of Cognitive-Behavioral Therapy and Psychodynamic Therapy in the Outpatient Treatment of Major Depression: A Randomized Clinical Trial

The efficacy of psychodynamic therapies for depression remains open to debate because of a paucity of high-quality studies. The authors compared the efficacy of psychodynamic therapy with that of cognitive-behavioral therapy (CBT), hypothesizing nonsignificant differences and the noninferiority of psychodynamic therapy relative to CBT. A total of 341 adults who met DSM-IV criteria for a major depressive episode and had Hamilton Depression Rating Scale (HAM-D) scores ≥14 were randomly assigned to 16 sessions of individual manualized CBT or short-term psychodynamic supportive therapy. Severely depressed patients (HAM-D score >24) also received antidepressant medication according to protocol. The primary outcome measure was posttreatment remission rate (HAM-D score ≤7). Secondary outcome measures included mean posttreatment HAM-D score and patient-rated depression score and 1-year follow-up outcomes. Data were analyzed with generalized estimating equations and mixed-model analyses using intent-to-treat samples. Noninferiority margins were prespecified as an odds ratio of 0.49 for remission rates and a Cohen's d value of 0.30 for continuous outcome measures. No statistically significant treatment differences were found for any of the outcome measures. The average posttreatment remission rate was 22.7%. Noninferiority was shown for posttreatment HAM-D and patient-rated depression scores but could not be demonstrated for posttreatment remission rates or any of the follow-up measures. The findings extend the evidence base of psychodynamic therapy for depression but also indicate that time-limited treatment is insufficient for a substantial number of patients encountered in psychiatric outpatient clinics.

Outcomes of Specialized Residential Treatment for Adults with Obsessive-Compulsive Disorder

Cognitive-behavioral therapy (CBT) utilizing exposure and response prevention for obsessive- compulsive disorder (OCD) has typically been studied in the context of time-limited treatment conducted in outpatient settings. However, in practice, patients vary in their response to such treatment, and some require more prolonged participation to obtain optimal benefit. An intensive residential program is one alternative for patients who do not improve in traditional outpatient treatment. This naturalistic study evaluated 46 patients with a primary diagnosis of OCD who received intensive residential treatment between 2004 and 2008. Patients entering the program completed assessments at admission and at discharge. Results indicated statistically significant improvements on all outcome measures, with 60.9% of patients meeting criteria for clinically reliable change in OCD severity and 37% achieving high end-state functioning. Specialized residential treatment seems effective for treatment-refractory OCD, although future controlled trials with larger samples are needed.

New Drugs and Drug News: The 411 and Implications for Palliative Care (TH313)

describe the role of the palliative care consultant caring for patients with kidney disease, provide prognostic tools, and provide a framework for engaging in discussions of treatment decisions. Content. The session includes an overview of the kidney disease trajectory and describes common triggers for palliative care consultation. Three common triggers for palliative care involvement along this trajectory will be explored and discussed: (a) discussions of dialysis initiation and withholding in seriously ill patients, (b) symptom management and medication strategies for patients both receiving and not receiving dialysis, and (c) end-of-life issues including dialysis withdrawal and dialysis access failure. We present a framework to elicit patient values and goals specifically addressing kidney disease treatment plans. This framework includes communicating the risks and benefits of dialysis in seriously ill patients and negotiating a care plan which may include withholding dialysis, withdrawing dialysis, or a time-limited treatment trial. Conclusion. By the end of the session, the palliative care provider will have gained new tools and understanding in caring for seriously ill patients with kidney disease. Participants will have an understanding of the unique challenges in treatment decision making; be able to list common symptoms patients experience, including treatment-related issues specific to certain symptoms; and gain an understanding of the prognostic factors and outcomes for different treatment paths. The palliative care provider will have the skill set to communicate care goals and treatment decisions with seriously ill patients with kidney disease.