Nonspecific Treatment Effects Research Articles

Actin Dynamics Is Essential for Myosin-Based Transport of Membrane Organelles

Actin filaments that serve as "rails" for the myosin-based transport of membrane organelles [1-4] continuously turn over by concurrent growth and shortening at the opposite ends [5]. Although it is known that dynamics of actin filaments is essential for many of the actin cytoskeleton functions, the role of such dynamics in myosin-mediated organelle transport was never studied before. Here, we addressed the role of turnover of actin filaments in the myosin-based transport of membrane organelles by treating cells with the drugs that suppress actin-filament dynamics and found that such a suppression significantly inhibited organelle transport along the actin filaments without inhibiting their intracellular distribution or the activity of the myosin motors. We conclude that dynamics of actin filaments is essential for myosin-based transport of membrane organelles and suggest a previously unknown role of actin-filament dynamics in providing the "rails" for continuous organelle movement resulting in the increased distances traveled by membrane organelles along the actin filaments.

The non-specific effects of group-based cognitive—behavioural treatment of chronic pain

Group-based cognitive-behavioural therapy (CBT) for chronic, non-malignant pain is recognized as the treatment of choice for patients with intractable pain problems. The core components of CBT pain treatment have been standardized, and meta-analyses have shown that that this form of intervention is effective. However, the psychotherapy literature points to a range of influences on treatment outcome that arise out of the process of treatment, rather than directly from the active treatment components. These so-called non-specific treatment effects include the composition of the group, the leadership style of the group leader, and the ways in which group dynamics are dealt with. Although CBT pain management programmes are conducted in a group format, and are therefore subject to similar kinds of influences to other forms of group treatment, these issues have not been discussed in detail in any previous literature. The present paper proposes a number of non-specific treatment factors that are likely to be associated with positive outcomes from CBT pain management programmes, and discusses ways in which these factors may be deliberately manipulated in order to maximize treatment effectiveness.

A Functional Magnetic Resonance Imaging Study of the Effects of Low Frequency Right Prefrontal Transcranial Magnetic Stimulation in Depression

The study aimed to explore the biological effects of low-frequency repetitive transcranial magnetic stimulation (LFR-TMS) treatment applied to the right prefrontal cortex, comparing this with the effects of high-frequency left-sided (HFL-TMS) in patients with treatment-resistant depression. Twenty-six patients with treatment-resistant depression were randomized to receive either daily LFR-TMS or HFL-TMS treatment for 3 weeks and underwent functional magnetic resonance imaging during a planning task before and after treatment. Patients responded clinically to both forms of treatment with no difference in the degree of response (F1,24 = 0.65;P > 0.05). Low-frequency repetitive transcranial magnetic stimulation resulted in no overall change in task-related activation. However, responders to LFR-TMS demonstrated a bilateral decrease in activity in middle frontal gyrus. In contrast, HFL-TMS produced an increase in activation in left precuneus with responders showing increased activation in several additional regions. Response to LFR-TMS is associated with a bilateral reduction in frontal activation that does not seem to be a nonspecific effect of treatment and differs from the response to HFL-TMS.

Contextualizing Specificity: Specific and Non-Specific Effects of Treatment

Modern medicine thrives on the ideal of specific diseases, and specificity has revolutionized thinking in clinical practice (e.g., psychiatry) as well as biomedical research (e.g., neuroscience). Different notions of specificity exist (e.g., clinical, biological, and behavioral). Behavioral specificity takes on new meaning in light of recent neuroimaging and genetic findings. Drawing on the metaphor of pharmacological specificity, we provide converging data suggesting that, at least for certain individuals, specific behavioral interventions can influence focal brain activations. Interpretation of these data paves the road to a more scientific strategy for studying the neural basis of suggestion and placebo response, and holds promise for the optimal matching of patient and treatment.

How Often Do SSRIs and Other New-Generation Antidepressants Lose Their Effect During Continuation Treatment?

A substantial number of patients who respond to antidepressants experience a relapse despite ongoing pharmacotherapy. The return of symptoms has been interpreted as a loss of the effectiveness of antidepressant activity. However, patients who initially improve while taking antidepressants include an admixture of true drug responders and placebo responders. Consequently, symptom return despite ongoing treatment may not represent a loss of drug effect because the patient may not have experienced a true drug response in the first place. The goal of the present report is to estimate the proportion of relapse attributable to the loss of true drug response versus a loss of placebo response. We reviewed continuation studies of new-generation antidepressants that began as placebo-controlled acute-phase studies. Studies were identified using MEDLINE (English-language articles published from 1980 to 2005 in 23 prespecified journals, using the search terms depression, continuation, and tachyphylaxis). Finally, we identified studies in reference lists of pertinent studies and review articles. Five studies were reviewed and selected according to the following criteria: continuation studies of new-generation antidepressants that began as placebo-controlled acute-phase studies. One of the studies was excluded from our analyses because it did not report response rates in the acute phase, and we could not find acute-phase response rates in related reports. Using the 2 formulas proposed by Quitkin and colleagues, we estimated the proportion of relapse attributable to the loss of true drug response versus the loss of response attributable to the nonspecific effects of treatment: The relapse rate in placebo responders was 24.1%, whereas the relapse rate in antidepressant responders was 7.4%. Two different methods of estimating relapse suggested that the majority of relapses in patients taking antidepressants during continuation treatment could be attributed to relapses occurring in patients who were not true drug responders. Most of the relapse rate during new-generation antidepressant continuation treatment may be due to relapse in patients who were not true drug responders, which suggests that loss of true drug response may be less common than previously thought.

Evaluating the Effectiveness of Your Medication Choice

One significant issue facing patients currently on antidepressants is the loss of effect that may occur with chronic use of the drug, ie, the so called “poop-out” effect. This article elaborates on this issue and discusses true drug responders versus placebo responders (those that have responded to the non-specific effects of treatment). Despite their response to treatment, there are no available clinical indicators to differentiate between these two types of responders.

Cognitive Neuroscience and Depression: Legitimate Versus Illegitimate Reductionism and Five Challenges

The provocative articles in this Special Issue underscore the potential of cognitive neuroscience to achieve fruitful integration across diverging levels of analysis. After a discussion of different forms of reductionism and the pragmatic, ideological, and cognitive obstacles standing in the way of achieving integrative explanatory pluralism, I outline five challenges to applying cognitive neuroscience to the study of depression and allied conditions: (1) comorbidity, (2) etiological heterogeneity, (3) ambiguity concerning causal primacy, (4) distinguishing state from trait markers, and (5) distinguishing specific from nonspecific treatment effects. Greater attention to these challenges should assist in bringing about consilience in the conceptualization of depression.

Psychotherapy for schizophrenia in the year 2030: prognosis and prognostication.

A number of psychotherapy techniques have been developed that, to varying degrees, have empirical support demonstrating favorable effects in the treatment of schizophrenia (or serious mental illness [SMI]). These techniques, and the research, vary with respect to theoretical origins, format, treatment targets, and expected outcome. A historical perspective informs understanding of this proliferation. One landmark in psychotherapy research was the recognition of common factors: different therapies embody common therapeutic factors not central to any one school. Importantly, insights about common factors reflected a better theoretical understanding of the psychotherapy process and led to the translation of learning and conditioning theories into the psychotherapy vocabulary. This resulted in the distinction between specific and nonspecific treatment effects, which pose present-day research questions such as how common and specific factors interact, and the differentiation of techniques for specific recipients. Because psychotherapy research progresses over the next 25 years, it will be important to develop a model that can answer such questions while incorporating the proliferation of specific modalities and the search for the "right recipe." This "search" will coincide with more attention to individual differences, it will incorporate quantitative modeling, and it will spawn an array of "tools" for treating problems associated with SMI. Because self-knowledge and personhood again become recognized dimensions of recovery, traditional psychodynamic principles and techniques will be revisited. This article explicates a 4-factor model that may be a view to the future.

Erleichtern Neuroimaging-Verfahren das Verständnis klinischer Akupunktureffekte?

One of the problems in assessing acupuncture efficacy has been the lack of a standardised placebo/control. Despite the lack of 'proof', acupuncture is widely used; hence it would seem that a large proportion of the public are not too concerned with the question of efficacy. Patients and researchers approach the issue of whether acupuncture "works" in an entirely different way. It may be that the management of chronic pain as a whole is largely context driven and non-specific. Therefore, research should focus on areas such as pragmatic/comparative trials and the non-specific effects of treatment. Improving our understanding of the neural mechanisms and substrates of acupuncture, placebo and non-specific effects might enable us to better define a "true placebo" and improve trial design. Imaging studies, however, need to be much more pragmatic. Because of the large overlap in areas of brain activated through acupuncture, pain, placebo and non-specific factors, separating these out in an attempt to pinpoint the mechanisms behind acupuncture will be difficult. Ultimately we need a balance between efficacy, comparative and mechanistic trials using imaging work to inform the whole picture. A broader view of research is therefore necessary to yield meaningful answers and we need to look at the whole package that acupuncture delivers.

Acoustic source measures for documenting outcomes of combined modality treatment of adductor spasmodic dysphonia

Spasmodic dysphonia (SD) is a voice disorder of neurogenic origin, wherein one or more intrinsic laryngeal muscles exhibit irregular and uncontrollable spasms. These spasms interfere with the production of perceptually normal voice. This paper presents a prospective, randomized, and placebo-controlled study to examine the effects of phonatory retraining (voice therapy) following Botox injections for ADSD. Thirty subjects were randomly assigned to 1 of 3 experimental groups: Botox only, Botox plus voice therapy, and Botox plus sham therapy. The sham therapy group was included in order to examine nonspecific treatment effects which may emerge as a result of close patient-therapist interaction during voice therapy for ADSD. Dependent variables of interest include acoustic source measures as well as voice-related quality of life, subject self-rating of voice, and duration of benefit between initial and repeat Botox injections. Source measures were typed according to National Center for Voice and Speech and signal typed into type 1, 2, and 3 signals. Voice breaks and frequency shifts were also measured. Preliminary results indicate that the combined modality treatment of voice therapy plus Botox has the more significant positive effect on source measures with trend toward more normal phonation or type 1 signal.

Trust and the sociology of the professions

There is a fast-growing literature on trust in health care, especially interpersonal trust, but also public or institutional trust, reflecting the growing awareness in both the research and policy communities of the importance of trust. At a general level, trust as part of the broader concept of social capital is related to people's health and well-being. Trust within provider-patient relations is important for its non-specific treatment effects. Finally, trust is also important for the smooth functioning of societal institutions. Rosemary Rowe and Michael Calnan1 discusses some of this literature in order to develop a ‘new agenda’ for research. I agree with most of what they write, but I think the research agenda needs further elaboration. Basically, I think that the developments Rowe and Calnan described in their contribution are much broader than just health care in three respects. First of all, the causes of erosion of trust are largely general societal developments. Second, these developments not only affect trust of patients in health care providers but also trust of health care providers in each other and trust in third parties. Thirdly, not only health care is affected, but also other areas …

The Role of Placebo and Nocebo Effects of Perioperative Administration of Sedatives and Opioids in Interventional Pain Management

The role of nonspecific treatment effects in the outcomes of patients receiving interventions for pain has been the subject of controversy and interest. While the administration of placebo and its effects have been widely studied, the role of placebo and nocebo effects of active agents administered prior to or during interventional techniques has not been explored. The evaluation of placebo and nocebo effects of sodium chloride solution and active agents (midazolam and fentanyl) administered during interventional techniques. Randomized, placebo-controlled, evaluation. A total of 360 patients were divided into three groups, with Group I receiving placebo, Group II receiving midazolam, and Group III receiving fentanyl. At 3 months, information was obtained with regards to their impressions or the experience of the study, compared to their previous experiences with the treatment and sedation. They were asked to rate their experience as better, worse, or no change compared to their previous experience. Between 13% to 30% of patients across all three groups of the study, rated their pain relief following injection as better than their previous experience. A smaller proportion, 3% to 8%, of patients in all three groups rated their experience following injection as worse than their previous experience. The majority of patients, 67% to 79%, regardless of group, described no significant differences as compared to their previous experiences with sedation and treatment for cervical or lumbar facet joint pain. In patients undergoing interventional procedures, sodium chloride solution, midazolam, and fentanyl produced placebo effects in 13% to 15%, 15% to 20%, and 18% to 30% of the patients respectively. Similarly, a nocebo effect was seen in 5% to 8% of the patients in the sodium chloride group, 8% of the patients in the midazolam group, and 3% to 8% of the patients in the fentanyl group. It is concluded that positive and negative effects may be seen either with placebo or active agents in 13% to 30% of the patients.

Is homeopathy a clinically valuable approach?

Homeopathy is a popular but implausible form of medicine. Contrary to many claims by homeopaths, there is no conclusive evidence that highly dilute homeopathic remedies are different from placebos. The benefits that many patients experience after homeopathic treatment are therefore most probably due to nonspecific treatment effects. Contrary to widespread belief, homeopathy is not entirely devoid of risk. Thus, the proven benefits of highly dilute homeopathic remedies, beyond the beneficial effects of placebos, do not outweigh the potential for harm that this approach can cause.

Women's Sexual Pain and Its Management

Approximately 15% of women have chronic dyspareunia that is poorly understood, infrequently cured, often highly problematic, and distressing. Chronic dyspareunia is an urgent health issue. To provide recommendations/guidelines concerning state-of-the-art knowledge for the assessment and management of women's sexual pain disorders. An international consultation, in collaboration with the major sexual medicine associations, assembled over 200 multidisciplinary experts from 60 countries into 17 committees. One six-member committee focused on women's sexual pain disorders, developing recommendations over a 2-year period. Expert opinion was based on grading of evidence-based medical literature, widespread internal committee discussion, public presentation, and debate. There is increasing evidence for the role of neuropathic pain mechanisms in the pathophysiology of sexual pain disorders. Empirical literature has demonstrated the comorbid presence of clinical psychopathology. With regard to the pathophysiologic role of the pelvic floor and sexual pain disorders, studies reveal that (i) differentiation between vaginismus and dyspareunia using clinical tools is difficult; (ii) vaginal spasms have not been identified; (iii) physical therapists can differentiate vaginismic women from matched controls based on muscle tone/strength differences; (iv) the traditional treatment of vaginismus with vaginal "dilatation" plus psycho-education, desensitization, and so forth is not evidence-based; (v) pelvic floor muscle tone/strength measures for women suffering from vulvar vestibulitis syndrome are intermediate between those of women with vaginismus and no-pain controls; and (vi) the pelvic floor musculature is indirectly innervated by the limbic system and highly reactive to emotional stimuli and states. Pelvic floor therapies for dyspareunia may be effective. Recommendations include (i) revising the definitions of vaginismus and dyspareunia; (ii) integration of treatment approaches; (iii) validation of nonspecific treatment effects; (iv) controlled studies to test interventions; and (v) sexuality education to help prevent sexual pain.

Bias Control in Trials of Bodywork: A Review of Methodological Issues

To review and summarize the methodological challenges in clinical trials of bodywork or handson mind-body therapies such as Feldenkrais Method, Alexander Technique, Trager Work, Eutony, Body Awareness Therapy, Breath Therapy, and Rolfing, and to discuss ways these challenges can be addressed. Review and commentary. Search of databases PubMed and EMBASE and screening of bibliographies. Published clinical studies were included if they used individual hands-on approaches and a focus on body awareness, and were not based on technical devices. Of the 53 studies identified, 20 fulfilled inclusion criteria. No studies blinded subject to the treatment being given, but 5 used an alternative treatment and blinded participants to differential investigator expectations of efficacy. No study used a credible placebo intervention. No studies reported measures of patient expectations. Patient expectations have been measured in studies of other modalities but not of hands-on mind-body therapies. Options are presented for minimizing investigator and therapist bias and bias from differential patient expectations, and for maintaining some control for nonspecific treatment effects. Practical issues with recruitment and attrition resulting from volunteer bias are addressed. Rigorous clinical trials of hands-on complementary and alternative therapy interventions are scarce, needed, and feasible. Difficulties with blinding, placebo, and recruitment can be systematically addressed by various methods that minimize the respective biases. The methods suggested here may enhance the rigor of further explanatory trials.

Design and Rationale of Controlled Study of Long-Term Methylphenidate and Multimodal Psychosocial Treatment in Children With ADHD

To describe the rationale, methodology, and sample characteristics of a dual-site treatment study (New York and Montreal) of children with attention-deficit/hyperactivity disorder (ADHD) conducted between 1990 and 1995. The hypotheses were that (1) methylphenidate combined with comprehensive multimodal psychosocial treatment was superior to methylphenidate alone in improving multiple functions and (2) the efficacy of the psychosocial intervention resulted from its specific components and not from nonspecific treatment effects. One hundred three children with ADHD (ages 7-9), free of conduct and learning disorders, who responded to methylphenidate, were randomized for 2 years to (1) methylphenidate treatment alone; (2) methylphenidate combined with multimodal psychosocial treatment that included parent training and counseling, academic assistance, psychotherapy, and social skills training; or (3) methylphenidate plus attention control treatment that excluded specific aspects of the psychosocial intervention. Children were switched to single-blind placebo after 12 months; methylphenidate was reinstituted when clinically indicated. Assessments included ratings by parents, teachers, children, and psychiatrists; school observations in academic and gym classes; and academic performance tests. Almost 80% of families completed the 2-year study. Companion papers present treatment effects. A comprehensive 2-year psychosocial treatment was delivered successfully to children with ADHD and their families.

Psychological Treatments for Irritable Bowel Syndrome: A Systematic Review and Meta-Analysis.

This study conducted a systematic review to assess the quality of existing literature on psychological treatments for irritable bowel syndrome and to quantify the evidence for their efficacy. Three independent reviewers (2 from England, 1 from the United States) coded the quality of 32 studies, 17 of which provided data suitable for meta-analysis. Meta-analysis of efficacy data (50% reduction of symptoms) gave an odds ratio of 12 (95% confidence interval = 5.56-25.96) and a number needed to treat of 2. Psychological treatments are, as a class of interventions, effective in reducing symptoms compared with a pooled group of control conditions. Questions regarding the relative superiority of specific psychological treatments and influence of active versus nonspecific treatment effects remain unanswered.

Dr. Casacalenda and Colleagues Reply

Back to table of contents Previous article Next article Letter to the EditorFull AccessDr. Casacalenda and Colleagues ReplyNICOLA CASACALENDA, M.D., J. CHRISTOPHER PERRY, M.P.H., M.D., and KARL LOOPER, M.D., NICOLA CASACALENDASearch for more papers by this author, M.D., J. CHRISTOPHER PERRYSearch for more papers by this author, M.P.H., M.D., and KARL LOOPERSearch for more papers by this author, M.D., Montreal, Que., CanadaPublished Online:1 Jun 2003https://doi.org/10.1176/appi.ajp.160.6.1187AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: We thank Dr. Rifkin for his thoughtful comments, in particular for emphasizing the importance of including a meaningful comparison group in any study comparing the efficacy of drugs and psychotherapy for the treatment of major depression. As discussed in our article, this approach “is the only safeguard against…inadequate implementation of pharmacotherapy, and nonspecific treatment effects” (p. 1357).Dr. Rifkin points out that the study by Elkin et al. (1989) showed no advantage for imipramine or either of two psychotherapies over placebo. However, this conclusion was based on analyses comparing changes in scores on the Hamilton depression scale from pretreatment to posttreatment within each of the treatment conditions. Secondary analyses examining remission, the focus of our review, found that the effects of both imipramine and interpersonal therapy—but not cognitive behavior therapy—were superior to those of placebo.Dr. Rifkin also concludes—erroneously in our view—that the study by Mynors-Wallis et al. (1995) “does not address the comparison of psychotherapy to drug treatment since the most relevant comparison (at 6 weeks) showed no drug effect for a well-proven drug treatment.” First, that study showed amitriptyline to be superior to placebo at 6 weeks on the basis of another analysis comparing mean scores on the Hamilton depression scale before and after 6 weeks of treatment. Second, the remission rates at 6 weeks (29% for subjects taking amitriptyline versus 3% for subjects taking placebo), although not significantly different (the groups were small), were clearly clinically meaningful. Finally, the results at 12 weeks consistently showed that both amitriptyline and problem-solving therapy were superior to placebo but not significantly different from each other.Finally, Dr. Rifkin expresses concern regarding lack of precision for the measures of efficacy in the study by Jarrett et al. (1999). Again, we believe this was attributable to the small group sizes in this study and in no way casts doubt on their finding of no difference in efficacy between phenelzine and cognitive therapy since they consistently showed, across five different stringent definitions of remission, that the remission percentages for both active treatments were almost identical to each other and approximately double that for the placebo group.Therefore, despite the limitations of each study reviewed, the remarkably consistent findings across these studies lead us to conclude, as we did in our original review, that “antidepressant medication…and psychotherapy…were more efficacious than control conditions, but there were no differences between active treatments” (p. 1355). FiguresReferencesCited byDetailsCited byNone Volume 160Issue 6 June 2003Pages 1187-1187 Metrics PDF download History Published online 1 June 2003 Published in print 1 June 2003

The non-specific effects of acupuncture treatment: When and how to control for them

The non-specific effects of acupuncture treatment: When and how to control for them

Sensory retraining is key to biofeedback therapy for formed stool fecal incontinence

Biofeedback is a nonsurgical treatment that reportedly produces good results in 65-75% of fecally incontinent patients. However, previous studies have not ruled out nonspecific treatment effects. It is also unknown whether biofeedback works primarily by improving the strength of the striated pelvic floor muscles or by improving the rectal perception. We aimed to 1) evaluate the efficacy of biofeedback in formed-stool fecal incontinence, 2) assess the relative contribution of sensory and strength retraining to biofeedback outcomes, and 3) identify patient characteristics that predict a good response to treatment. Twenty-four patients with frequent (at least once a week) solid-stool incontinence were provided with three to four biofeedback sessions. They were taught to squeeze in response to progressively weaker rectal distentions. Patients were re-evaluated by anorectal manometry and symptom diary 3 months after completing training and by diary and interview 6-12 months after training. Seventeen (71%) were classified responders; 13 became continent and four reduced incontinence frequency by at least 75%. Clinical improvements were maintained at 12-month follow-up. At 3-month follow-up, responders had significantly lower thresholds for perception of rectal distention and for sphincter contraction, but squeeze pressures did not significantly differ from those of nonresponders. Baseline measures that predicted a favorable response were sensory threshold (50 ml or less), urge threshold (100 ml or less), lower threshold for sphincter contraction, and lower threshold for the rectoanal inhibitory reflex; neither anal squeeze pressure nor severity of incontinence predicted treatment outcome. In solid-stool fecal incontinence biofeedback training effects are robust and seem not to be explained by expectancy or nonspecific treatment effect. Sensory retraining appears to be more relevant than strength training to the success of biofeedback.