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Top Research Findings That Can Change Clinical Practice

Top Research Findings That Can Change Clinical Practice

Treatment studies for clinical practice

Psychiatrists and other clinical providers are under increasing pressure to stay current. With the fast growth of knowledge, the challenge to keep up with the ever-growing body of information is greater than ever. There is an emerging realization that, as clinical providers, we need help in sorting and evaluating the quality of information before we can apply it to clinical practice. Otherwise, when facing the overload of information we tend to take the first or the most easily accessed without taking into account the quality of the information. As a result, quality of care suffers and costs millions of dollars annually in problems associated with underuse, overuse, and misuse. We need an efficient and effective system of how to sort, evaluate, and use information.

In an effort to sort and evaluate published research that is ready for clinical practice, we undertook a 3-step process:

• We searched the literature published between June 1, 2010 and May 31, 2011for relevant study findings.

• We asked various psychiatric groups and colleagues the following question: Of the research published from June 1, 2010 through May 31, 2011, which had the most impact on the clinical practice of psychiatry?

• We looked for appraisals in post-publication reviews such as Faculty of 1000 Factor, Evidence-Based Mental Health, commentaries in peer-reviewed journals, etc.

The papers were chosen based on our judgment of their clinical relevance/applicability, ie, their “clinical readiness.” Here we present summaries of the “top” papers that were chosen (the order in which the articles appear is arbitrary). The abstracts are available on PubMed, and many have full text available online.

Treatment
Blader JC, Pliszka SR, Jensen PS, et al. Stimulant-responsive and stimulant-refractory aggressive behavior among children with ADHD. Pediatrics. 2010;126:e796-e806.
A total of 65 preadolescent children with treatment-resistant ADHD and marked aggressiveness were given systematic stimulant treatment. Often this population ends up with adjunctive antipsychotic medication. This study found that approximately 50% of these children would show remission of ADHD symptoms and aggressiveness with the use of higher doses of stimulants than are frequently used in primary care. Among children whose aggressive behavior developed in the context of ADHD and who had insufficient response to previous stimulant treatment in routine clinical care, systematic, well-monitored titration of stimulant monotherapy affected the course of both ADHD and associated aggression. If primary care physicians were comfortable in using higher doses of stimulants to treat nonresponsive aggressiveness, the use of antipsychotics to reduce aggression in preadolescents would be substantially reduced.

Papakostas GI, Mischoulon D, Shyu I, et al. S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: a double-blind, randomized clinical trial. Am J Psychiatry. 2010;167:942-948.
In a randomized, double-blind trial, 73 patients with MDD who did not respond to SSRI treatments were randomly assigned to a placebo group or to an augmentation group of SAMe (1600 mg/d) for 6 weeks. Both groups were maintained on stable doses of the SSRIs they were already taking. Intent-to-treat analysis of Hamilton Depression Rating Scale (HAM-D) changes compared the two groups on percentage who had symptom remission and percentage who had at least a 50% reduction on the HAM-D score.

There were no differences in the number of adverse effects or patients who discontinued because of lack of efficacy. Almost 36% of patients in the SAMe augmentation group had symptom remission compared with 12% in the placebo group, resulting in a number needed to treat (NNT) of 4.2. More than 46% in the SAMe group showed greater than 50% improvement compared with 18% in the placebo group (NNT = 3.5). While requiring replication and extension for longer treatment durations and follow-up, the size of the effect of SAMe augmentation seems clinically significant, especially when compared with FDA-approved augmenting agents aripiprazole and olanzapine.

Emslie GJ, Mayes T, Porta G, et al. Treatment of Resistant Depression in Adolescents (TORDIA): week 24 outcomes. Am J Psychiatry. 2010;167:782-791.
This is 1 of 4 articles that report outcomes of the TORDIA trial. This trial was made up of 334 children and adolescents aged 12 to 18 years with treatment-resistant depression. They were randomized to 1 of 4 initial treatment arms: an SSRI different from the one that had failed; venlafaxine; a different SSRI plus cognitive-behavioral therapy (CBT); or venlafaxine plus CBT. Ratings of treatment outcomes were double-blind. After 12 weeks, responders were maintained on the same treatment for another 12 weeks. Nonresponders were unblinded as to antidepressant, and treatments could be switched to different medications and/or CBT or augmenting agents could be added. Remission and relapse rates at the end of 24 weeks did not differ between treatments. Despite selection for treatment resistance, 39% of patients achieved remission after 6 months of treatment. Nonresponders had some improvement during the first 6 weeks but seemed to plateau; responders continued to improve throughout the 24-week trial.

Generally, early response predicted remission. Responders had close to a 50% reduction in symptom severity scores by the end of 6 weeks, while nonresponders had improved by only 25%. Among nonresponders, augmenting treatment within the first 12 weeks facilitated remission, while augmentation within the last 12 weeks did not. Other baseline and week-12 variables, including lower severity of symptoms, low family conflict, and the absence of substance abuse, were found to predict remission. Twenty percent of those who had symptom remission by week 12 relapsed by week 24. The importance of recognizing nonresponders during the first 6 weeks and augmenting treatment early is emphasized.

Vitiello B, Emslie G, Clarke G, et al. Long-term outcome of adolescent depression initially resistant to selective serotonin reuptake inhibitor treatment: a follow-up study of the TORDIA sample. J Clin Psychiatry. 2011;72:388-396.
The second paper by the TORDIA group presented follow-up data from 48 and 72 weeks after the trial started. Usual community care began after the initial 24-week trial. Remission rates continued to improve, reaching more than 60% after 72 weeks. For responders, symptom levels continued to drop over the entire 72-week period, while for nonresponders symptom level improvements had essentially stopped by 6 weeks. Findings from long-term follow-up reinforce the importance of treatment response during the first 6 weeks and not waiting to initiate treatment augmentation or change, especially if previous treatment resistance has been shown.

Sakolsky DJ, Perel JM, Emslie GJ, et al. Antidepressant exposure as a predictor of clinical outcomes in the Treatment of Resistant Depression in Adolescents (TORDIA) study. J Clin Psychopharmacol. 2011;31:92-97.
In this TORDIA follow-on trial, the data came from the same 334 adolescents with SSRI-resistant MDD who were randomized to venlafaxine with or without CBT augmentation or a different SSRI with or without CBT augmentation. All participants received family psychoeducation and supportive management. At weeks 6 and 12, blood levels of the medication and major metabolites were measured in all groups to test whether the extent of response to treatment was related to these blood levels. Dosages were increased for patients who had not improved. Results were mixed in that patients whose medication was switched to citalopram or fluoxetine who had higher plasma levels at 6 weeks were more likely to have improved by 12 weeks, while no such relationship was seen with venlafaxine, paroxetine, or sertraline. This may have been because plasma levels for these latter medications were relatively higher at 6 weeks so that there was something akin to a ceiling effect.

This is the first study that showed a relationship between plasma levels and treatment response in adolescent depression and suggests that plasma levels, particularly for citalopram and fluoxetine, will help decide whether a switch to another SSRI or a dosage increase should be tried.

Shamseddeen W, Asarnow JR, Clarke G, et al. Impact of physical and sexual abuse on treatment response in the Treatment of Resistant Depression in Adolescent Study (TORDIA). J Am Acad Child Adolesc Psychiatry. 2011;50:293-301.
In this TORDIA trial, the original 334 participants were randomly assigned to 4 groups: 2 groups received a different SSRI, and 2 received the SNRI venlafaxine. One group of each medication received additional CBT. In the 12-week study, participants in each treatment group with a history of sexual or physical abuse were compared with group members who had no such history.

The groups that received additional CBT showed greater treatment response (62.8%) than the pharmacotherapy-alone groups (37.6%), but only for patients with no reported history of abuse. In patients with histories of physical abuse, those who received the combination of pharmacotherapy plus CBT had lower response rates (18.4%) than those who received pharmacotherapy alone (52.4%), while histories of sexual abuse had no differential effect on response rates (48.3% and 42.3%, respectively).

These findings suggest that until the mechanisms of effects of physical and sexual abuse are better understood, alternatives to CBT augmentation of antidepressants for adolescents with treatment-resistant depression should be considered when there is a history of physical abuse. On the other hand, CBT augmentation should be considered for adolescents with treatment-resistant depression who do not have a history of abuse.

Prognosis
Foti DJ, Kotov R, Guey LT, Bromet EJ. Cannabis use and the course of schizophrenia: 10-year follow-up after first hospitalization. Am J Psychiatry. 2010;167: 987-993.
This is a report of a cohort study that followed 229 patients with schizophrenia, schizoaffective disorder, or schizophreniform disorder within 6 months of their first hospitalization. Their use of cannabis (1 month or 6 month use) and their positive (Scale for the Assessment of Positive Symptoms) and negative (Scale for the Assessment of Negative Symptoms) symptom levels were monitored at baseline and 6 months, and 2, 4, and 10 years later. SCID (Structured Clinical Interview) and GAF (Global Assessment of Functioning) data were also obtained.

At the 10-year assessment, 82% of participants (188) provided at least partial data. At baseline 62% of patients had a history of cannabis use, although only 10% had used cannabis within the month preceding baseline. While the subset of users changed from one assessment point to another, the numbers of cannabis users at each assessment point were between 10% and 18%. At each point, those who had used preceding the assessment showed higher levels of psychotic symptoms than those who had not used, although only the positive psychotic symptom subscale levels were predicted at statistical significance in a multiple regression.

Use of cannabis before the first hospitalization was associated with an earlier age of symptom onset. Use of cannabis after hospitalization was associated with higher psychotic symptom levels. Educating patients and family members about the potential positive effects of reducing cannabis use on psychotic symptoms and helping patients with schizophrenia develop strategies to avoid cannabis use is indicated for a better prognosis.

Prevention
Rapee RM, Kennedy SJ, Ingram M, et al. Altering the trajectory of anxiety in at-risk young children. Am J Psychiatry. 2010;167: 1518-1525.
Prevention is such an appealing concept, particularly when thinking about preventing the development of potentially lifelong disorders in children. Rapee and colleagues provide compelling evidence that brief intervention (6-session parent training) to reduce overprotection of their behaviorally inhibited children, reduced the incidence of anxiety disorders in their children over a 3-year follow-up period. The randomized controlled trial (n = 73 in both intervention and monitoring control group), utilized scores above 30 on the approach subscale of the Short Temperament Scale for Children, completed by mothers of preschool children, to indicate social withdrawal in their children.

The mother and child pairs were then exposed to various social interaction opportunities in a laboratory setting. Children who tended to avoid social interaction with strangers, another child, and with lab assistants were randomized to either the brief intervention group or a monitoring-only group. Blind diagnostic assessment interviews were conducted to establish baseline disorders and their severity. In the brief intervention group, 6 sets of parents were given 6, 90-minute parenting sessions that covered the nature of anxiety, parent management techniques, the role of over-protection in fostering anxiety, cognitive restructuring of the parents’ anxieties, and training in exposure hierarchies. The training was completed over a 10-week period.

Both groups showed declines in the number of children with diagnosable anxiety disorders and in the severity of anxiety symptoms, although the parent training groups showed significantly fewer children with anxiety disorders and a greater reduction in symptom severity. The intervention was flexible in that it could be developed in schools, community settings, or in practice settings, and the size of the prevention effect grew over the 3-year follow-up period.

Wickramaratne P, Gameroff MJ, Pilowsky DJ, et al. Children of depressed mothers 1 year after remission of maternal depression: findings from the STAR*D-Child study. Am J Psychiatry. 2011;168: 593-602.
This study extends previous findings that treating depressed mothers to remission reduces or prevents psychiatric symptoms in their children. The response to citalopram treatment of depressed mothers who participated in the STAR*D study was evaluated in 80 children. The child’s symptoms were assessed every 3 months for 1 year after symptom remission in the mother, or for 2 years if there was no symptom remission.

Children of mothers with quick (0-3 months, n = 36), slow (3-12 months, n = 28), or no (n = 16) symptom remission were compared for changes in their symptoms or probability of developing symptoms. Children of mothers whose depression symptoms remitted quickly were the most likely to show reductions in symptoms or to avoid the development of new symptoms. Children of mothers whose depression never remitted were more likely to show increases in symptoms, particularly externalizing symptoms, and to develop new symptoms. Children of mothers whose depression remitted slowly were less likely to develop new symptoms and more likely to improve than children of non-remitters, but more likely to develop new symptoms and less likely to improve than children of quick remitters.

This reinforces the importance of treating the parents of depressed children, and treating depressed parents to remission to prevent increases in their child’s symptoms and the development of new ones.

Baldessarini RJ, Tondo L, Ghiani C, Lepri B. Illness risk following rapid versus gradual discontinuation of antidepressants. Am J Psychiatry. 2010;167:934-941.
Patients treated with antidepressant medications to remission for MDD (224), panic disorder (75), or bipolar disorders (I, 37; II, 62) were followed for 12 to 100 months after they elected to discontinue their medications. The patients who chose to discontinue their medications in a week or less were compared with those who discontinued over at least a 2-week period. The quickly discontinued group showed significantly higher rates of symptom recurrence after shorter periods of time than the group who discontinued more slowly. While there are design flaws that weaken the findings, this adds to the growing evidence that rapid discontinuation makes symptom return more likely in general, and specifically for depressive symptoms. Patient counseling to avoid rapid discontinuation may serve to extend the duration of symptom remission or improvement.

Large M, Sharma S, Compton MT, et al. Cannabis use and earlier onset of psychosis: a systematic meta-analysis. Arch Gen Psychiatry. 2011;68:555-561.
This meta-analysis included 83 studies (substance users = 8167; nonsubstance users = 14,352) that examined the relationship between drug and alcohol use and age of onset of psychotic disorders. Several studies had demonstrated a relationship between cannabis use and earlier psychiatric hospital admission or diagnosis of schizophrenia. This meta-analysis addressed several methodological weaknesses of previous studies, including looking for psychotic symptom onset rather than first diagnosis, comparing cannabis to other psychoactive substances, including nonschizophrenia psychotic diagnoses, and focusing on young onset patients rather than bias connected to older patients who are less likely to use cannabis.

Age of onset of psychotic disorders, including schizophrenia was 2.7 years earlier among cannabis users than patients who had not used cannabis, while there were no differences in age of onset with alcohol use. The principle implication involves the possible beneficial effects of educating the community or at-risk families and individuals of the possible prevention or delay of psychotic disorders if cannabis use is avoided. Prevention or delay of psychosis onset by educating at-risk families or individuals to avoid cannabis use have not yet been demonstrated, however.

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