Ree Dawson

Dynamic treatment regimes: practical design considerations

Background Clinical management of chronic disease requires a dynamic treatment regime (DTR): rules for choosing the new treatment based on the history of response to past treatments. Estimating and comparing the effects of DTRs from a sample of observed trajectories of treatment and outcome depends on the untestable assumption that new treatments are assigned independently of potential future responses to treatment, conditional on the history of treatments and response to date (“sequential ignorability”). In longitudinal observational studies, sequential ignorability must be assumed, while randomization of dynamic regimes can guarantee it. Methods Using several clinical examples, we describe the simplest randomized experimental designs for comparing DTRs. We begin by considering an initial treatment A and a second treatment B, and discuss how a dynamic treatment regime that starts with A and leads (sometimes) to B, might be compared to either fixed treatment A or B. We also illustrate the problem of finding the optimal sequence of treatments in a DTR, when there are several choices. We describe and contrast two ways of incorporating randomization into studies to compare such regimes: baseline randomization among DTRs versus randomization at the decision points (sequentially randomized designs). Conclusions We discuss estimation and inference from both baseline randomized and sequentially randomized designs and conclude with a discussion of the differences between the experimental and observational approaches to optimizing and comparing dynamic treatment regimes.

A design for testing clinical strategies: biased adaptive within‐subject randomization

We propose a method for assigning treatment in clinical trials, called the ‘biased coin adaptive within‐subject’ (BCAWS) design: during the course of follow‐up, the subjects response to a treatment is used to influence the future treatment, through a ‘biased coin’ algorithm. This design results in treatment patterns that are closer to actual clinical practice and may be more acceptable to patients with chronic disease than the usual fixed trial regimens, which often suffer from drop‐out and non‐adherence. In this work, we show how to use the BCAWS design to compare treatment strategies, and we provide a simple example to illustrate the method.

Alcohol and cannabis use in schizophrenia: effects of clozapine vs. risperidone

BACKGROUND Alcohol and cannabis use disorders worsen the course of schizophrenia. While the typical antipsychotics are of limited value in controlling substance use in schizophrenic patients, previous studies suggest that the novel antipsychotic clozapine (CLOZ) may decrease their substance use. We describe a retrospective study of the effects of the novel antipsychotics risperidone (RISP) and clozapine on alcohol and cannabis use in patients with schizophrenia or schizoaffective disorder and comorbid alcohol and/or cannabis use disorder. METHOD This study involved retrospective assessment of abstinence (cessation of alcohol and cannabis use) in 41 patients treated with either risperidone (n=8) or clozapine (n=33) for at least 1 year. In 32 of these 41 patients, information was available on whether abstinence occurred during the 1-year period. RESULTS Abstinence rates were significantly higher in patients treated with clozapine than in those treated with risperidone (54% vs. 13%, p=0.05). The nine patients treated for at least 1 year, but excluded from the analysis because time of cessation of use was not known, had all stopped alcohol/cannabis use during clozapine treatment. DISCUSSION While the limitations of this retrospective study must be recognized, the data suggest that comorbid patients treated with clozapine are more likely to abstain from alcohol and cannabis use than are those treated with risperidone. Further prospective studies will be required to confirm these intriguing results.

Sexual Harassment and Assault as Predictors of PTSD Symptomatology Among U.S. Female Persian Gulf War Military Personnel

Rates and sequelae of sexual harassment and assault among women in a wartime military sample were examined. A second goal was to explore the comparative impacts of these stressors and combat exposure on posttraumatic stress disorder (PTSD) symptomatology. Army women (n=160) were interviewed on return from the Persian Gulf War and again 18 to 24 months later. Rates of sexual assault (7.3%), physical sexual harassment (33.1%), and verbal sexual harassment (66.2%) were higher than those typically found in civilian and peacetime military samples. Sexual assault had a larger impact on PTSD symptomatology than combat exposure. Frequency of physical sexual harassment was significantly predictive of PTSD symptomatology. Furthermore, the number of postwar stressful life events mediated the relationship between physical sexual harassment and symptomatology but was not related to combat exposure. Sexual assault, sexual harassment, and combat exposure appear to be qualitatively different stressors for women, with different correlates and mechanisms of action.

Flexible treatment strategies in chronic disease: clinical and research implications.

Multiple treatments are available for nearly all the mood disorders. This range of treatment options adds a new dimension of choice to clinical decision making. In addition to prescribing the best initial treatment, clinicians should have an algorithm for deciding if and when to make subsequent changes in treatment to take advantage of second-line treatment options when necessary. This article aims to 1) show that a wide variety of clinical decisions can be framed as choices among adaptive (within-patient) threshold-based strategies or algorithms, illustrating the generality of the concept; 2) illustrate two ways to design randomized clinical trials to compare treatment strategies with each other to decide which strategy is best; and 3) discuss some of the advantages offered by these designs, in terms of both patient acceptability and adherence to experimental protocols.

Antipsychotic medication, prolactin elevation, and ovarian function in women with schizophrenia and schizoaffective disorder

Some, but not all, antipsychotics elevate serum prolactin. Antipsychotic-induced hyperprolactinemia is thought to account for high rates of menstrual dysfunction and diminished estrogen levels in women with schizophrenia. However, few studies have directly assessed the relationships between prolactin, menstrual function, and ovarian hormone levels in this population. Sixteen premenopausal women with schizophrenia and schizoaffective disorder, eight treated with an antipsychotic with prolactin-elevating potential (five with typical antipsychotics and three with risperidone) and eight treated with an antipsychotic with prolactin-sparing potential (seven with olanzapine and one with clozapine), were studied for eight weeks. Data were collected on menstrual functioning and on serum prolactin, estradiol, and progesterone levels, and were compared between subjects who received an antipsychotic with prolactin-elevating potential and an antipsychotic with prolactin-sparing potential, and between subjects with hyperprolactinemia (N=6) and normoprolactinemia (N=10). Additionally, peak ovarian hormone levels were compared to normal values. While mean prolactin levels of subjects who received an antipsychotic with prolactin-elevating potential were significantly greater than those of subjects who received an antipsychotic with prolactin-sparing potential, there were no differences in rates of menstrual dysfunction or in ovarian hormone values between the two groups. Additionally, similar rates of menstrual dysfunction and ovarian hormone values were observed between the hyperprolactinemic and normoprolactinemic subjects. Moreover, irrespective of medication type or prolactin status, most subjects had peak estradiol levels below normal reference values for the periovulatory phase of the menstrual cycle. While our sample size is small, warranting the need for further investigation, the findings of this preliminary study suggest that antipsychotic-induced hyperprolactinemia, alone, may not adequately explain the observed ovarian dysfunction in women with schizophrenia.

Maintenance strategies for unipolar depression: an observational study of levels of treatment and recurrence

BACKGROUND This paper analyses data from a large observational study of the course of affective illness to provide insight into the duration and dose of effective maintenance therapies. METHODS The data are 236 unipolar patients who had received antidepressants during recovery and were followed for affective recurrence for up to 5 years. Using data on the naturally selected somatic treatments, we have conducted analyses that adjust for the potential confounding effects of prognosis and treatment intensity to estimate the causal effect of level of medication on the course of recurrence. RESULTS The results of these analyses show that it is important for patients to remain on the level of somatotherapy used to treat the acute episode for the initial 8 months after symptoms have abated. After that time, the rate of recurrence for patients with fewer than five previous episodes is approximately 1% per week or less at all levels of medication (including discontinuation). Patients who had experienced more than several recurrences are at greater risk of recurrence and continue to benefit from any level of medication during the first year after recovery. CONCLUSIONS The CDS analyses reported here suggest that effective maintenance strategies for all but highly recurrent patients may be a middle road, opting for full-dose strategies of limited duration. These results have implications at both the policy and the clinical level, given the need to consider both monetary and nonmonetary costs (side-effects) associated with continued pharmacotherapy during remission. LIMITATIONS The observational design of the CDS limits the degree to which cause and effect relationships can be inferred from the observed associations.

Course of treatment received by depressed patients

Using data from an observational study of affective disorders, we describe the rates of transition among levels of antidepressant treatment for subjects with Major Depressive Disorder (MDD), and relate these changes to changes in clinical status. We report on the treatment received during the first 10 years of follow-up in the Collaborative Depression Study by 555 patients with a diagnosis of MDD of at least one months duration. This work extends the initial examination of treatment received during the first eight weeks after entry into this study that showed depressed patients to be on low levels of treatment. Multiplicative intensity models which generalize survival analysis models were used to analyse these data. Description of the course of treatment of these depressed patients shows that low levels of treatment persist for these patients across subsequent episodes, and that these episodes, like the index one, are characterized by extended time in a symptomatic subcriterion state after acute symptoms have improved. These long-term descriptions of treatment support the initial hypothesis that these CDS patients were undertreated. The long-term tendency toward undertreatment seems to persist even as newer treatments become available and widely accepted in practice.

A Randomized Trial of Clozapine Versus Other Antipsychotics for Cannabis Use Disorder in Patients With Schizophrenia

Objective: Cannabis use disorder is the most common co-occurring drug use disorder in people with schizophrenia and is associated with poor outcomes. The authors launched a randomized controlled trial to assess the impact of clozapine compared with treatment as usual on cannabis use in patients with schizophrenia and co-occurring cannabis use disorder. Methods: Thirty-one patients with schizophrenia and co-occurring cannabis use disorder were randomly assigned to switch to clozapine or to stay on their current antipsychotic and were then followed weekly for 12 weeks. Blinded raters assessed participants weekly with the Timeline Followback for substance use and the expanded Brief Psychiatric Rating Scale for symptoms. Longitudinal random effects models were used to investigate the time-varying differences in cannabis use and other outcomes between the treatment as usual and clozapine groups. Results: The two groups differed in average intensity of cannabis use by approximately 4.5 joints/week, with lesser use in the clozapine group (t = −1.77; df = 28.5; p = .086; effect size ∼ 0.6). Symptoms and functioning were not different between the two groups. Conclusions: Clozapine may reduce cannabis use among patients with schizophrenia and co-occurring cannabis use disorder. Further controlled trials are warranted.

Clozapine reduces alcohol drinking in Syrian golden hamsters.

Alcohol abuse contributes substantially to the overall morbidity of schizophrenia. While typical antipsychotic medications do not limit alcohol use in patients with schizophrenia, emerging data suggest that the atypical antipsychotic clozapine does. To further elucidate the effects of these antipsychotics on alcohol use, we initiated a study in alcohol-preferring rodents. Syrian golden hamsters were given free-choice, unlimited access to alcohol. Nine days of treatment (s.c. injection) with clozapine (2-4 mg/kg/day), but not haloperidol (0.2-0.4 mg/kg/day), reduced alcohol drinking. Clozapine reduced alcohol drinking by 88% (from 11.3+/-1.7 to 1.4+/-0.2 g/kg/day) while increasing both water and food intake. Alcohol drinking gradually (during 24 days) returned toward baseline in the clozapine-treated animals when vehicle was substituted for clozapine. Further increasing the doses of haloperidol (0.6-1.0 mg/kg/day) had no effect on alcohol drinking; moreover, very low doses of haloperidol (0.025-0.1 mg/kg/day) tested in separate groups of hamsters also had no effect on alcohol drinking. This study demonstrates that clozapine, but not haloperidol, can effectively and reversibly decrease alcohol consumption in alcohol-preferring hamsters. The results are compatible with the observations that clozapine, but not haloperidol, limits alcohol use in patients with schizophrenia. These data further suggest that clozapine may serve as a prototype for developing novel treatments for alcohol abuse.