The multi-level outcome study of psychoanalysis for chronically depressed patients with early trauma (MODE): rationale and design of an international multicenter randomized controlled trial

Chronic depression is a common disorder. Population lifetime prevalence estimates are 3–15% for major depression [1‐6] and 3–4% for dysthymia [7‐10], with 20–33% of all depressive illness becoming chronic [3, 11]. Persons whose depression is chronic tend to have more severe symptoms, more frequent recurrences, lower remission rates, longer courses of medication treatment [12, 13], and higher rates of psychiatric and physical co-morbidities [2, 3, 12, 14] compared with depressive episodes of shorter duration. Recent epidemiological findings suggest that chronic depression is associated with a series of potentially modifiable risk factors, such as increase in suicidal ideation/attempts during the most severe episode, higher levels of neuroticism, lower levels of extraversion and lower levels of informal help-seeking behavior compared to nonchronic MDD, that are accessible via psychotherapies that can improve the course of chronic depression [15]. Chronic depression entails enormous direct and indirect costs for health care systems (see e.g. [16]).

Patients with chronic depression require tailored psychotherapeutic treatments that address their specific clinical needs [17]. Meta-analyses show that various forms of short-term therapy are similarly successful in reducing symptom severity but do not significantly reduce relapse rates [11, 18‐27]. Increasing evidence suggests that these patients require more intensive and longer treatments to achieve sustained symptomatic and functional improvement [17, 28‐31].

Only a small number of studies, however, have assessed the effectiveness of long-term therapies for chronic depression [24, 25, 32‐40]. We refer to two more recent studies that assessed the effectiveness of long-term psychoanalytic psychotherapy for chronic depression in particular. One was The Tavistock Adult Depression Study (TADS), which was a randomized controlled trial of 129 patients with chronic depression of at least 2 years duration. It assessed the effectiveness of 18 months of long-term psychoanalytic psychotherapy (LTPP) as an adjunct to treatment-as-usual (TAU), compared to TAU alone. The TAU group was treated with interventions as directed by the referring practitioner, which could include referral to other specialists in accordance with UK guidelines of the National Institute for Clinical Excellence (National Institute for Health and Clinical Excellence [41]. Both clinician- and self-reported depression severity, as well as measures of social adjustment, showed significantly greater improvement in the LTPP group [39].

The second was the LAC Study (Langzeitbehandlungen chronisch depressiver Patienten), which compared the effectiveness of long-term cognitive-behavioral therapy (CBT) vs long-term psychoanalytic therapy (PAT) in 252 chronically depressed patients. The study also considered the effects of preferential or randomized allocation [42]. As is the practice of the two forms of psychotherapeutic interventions in Germany, the number of sessions offered to the patient varied. During the first year of treatment, CBT patients received a mean (SD) of 32.5 (9.0) therapy sessions while PAT participants received a mean (SD) of 80.4 (27.8) sessions. Both psychotherapies and both allocation conditions showed a clinically relevant and highly significant reduction of depressive symptoms over 1, 2, and 3 years. After 3 years, self-rated full remission rates were 45% (BDI ≤ 12), and clinician-rated full remission rates were 61% (QIDS-C ≤ 5). The effect sizes were very large (d = 1.78 for the BDI); d = 2.12 for the QIDS-C). These effect sizes and full remission rates were better compared to other studies [11, 29, 34]. As in other studies, researchers found no significant difference between PAT and CBT for symptom reduction 3 years after beginning treatment.

In contrast to the original hypotheses PAT produced a statistically significant reduction in depressive symptoms already after one year of treatment. In addition, three years after the start of treatment, significantly more patients in psychoanalytic treatment showed increased awareness of unconscious fantasies and conflicts, so-called “structural changes, in personality organization compared to patients in cognitive-behavioral treatments [30]. Clinical observations confirmed that these changes were more pronounced in high-frequency treatments than in low-frequency treatments.

An unexpected, post hoc finding of the LAC study was that more than 80% of chronically depressed patients participating in the study suffered from early trauma, and that these patients responded especially well to high frequency psychoanalytic psychotherapy, often achieving sustained, structural changes in personality organization. A review of clinical observations revealed that patients in high-frequency psychoanalytic treatments were more likely to be successful in therapeutically regaining the primal trust in a helping Other and their own self agency that had collapsed as a result of traumatization than in low frequent treatments (see e.g. [43‐46]; or “epistemic trust” – see [47]. These clinical effects were connected to some extent to "structural changes" in personality organization as assessed using the Operationalized Psychodynamic Diagnosis (OPD) [29, 30, 47‐49]. This clinical finding was consistent with a previous study showing that chronically depressed patients who had a history of early childhood trauma achieved significantly higher remission rates with psychotherapy monotherapy than with nefazodone monotherapy [50], leading to the conclusion of the study investigators that chronically depressed patients who have a history of early trauma may differ in some fundamental yet undefined way from those without a history of early trauma [50]. A meta-analysis [51] also showed that neglect and emotional abuse are correlated with adult depression. In the LAC Study emotional neglect, as measured by the CTQ, was the most frequent form of childhood trauma of the chronic depressed patients and influenced the severity of the depression in this group of patients (see e.g. [52]).

A meta-analysis of including a variety of psychotherapies for chronic depression reported a strong association for symptomatic improvement with the number of treatment sessions [53]. Moreover, both a higher number of weekly psychoanalytic sessions, as well as a more pronounced application of psychoanalytic treatment techniques, increased the effectiveness of psychotherapy in patients with major depression [54]. Session frequency has also been identified as an important factor in the efficacy of psychotherapy in general. An overview focusing on the difference between psychoanalysis and psychoanalytic psychotherapy suggested that the success of therapy does not correlate most with the duration of the treatment, but with the frequency of sessions [31]. These findings suggest that a higher treatment frequency is more effective than lower treatment frequency in reducing symptoms. In sum, findings suggest that higher session frequency may offer an advantage that goes beyond the total number of sessions in the psychoanalytic psychotherapy of depression. Still unknown is whether a similar frequency effect is present in the psychoanalytic treatment of depression that is chronic.

Several investigators have used brain imaging technologies to study the associations of psychotherapies with measures of brain structure and function [55], including in depressed patients [56‐66]. Lueken & Hahn [67] describe two general approaches that have been employed thus far: 1) the longitudinal study of brain changes, comparing pre- to post-treatment brain measures, associating those changes with measures of treatment response to psychotherapy; and 2) associating pre-treatment brain measures with treatment outcomes, such as depressive symptom reduction, to identify brain predictors of treatment response. Most of these studies have been naturalistic (without employing randomization between treatment arms) and they often have been uncontrolled (without a comparison group). Three meta-analyses summarized studies on treatment effects on clinical and brain-based predictors [68‐70]. Cristea et al. [71] combined a meta-analysis with a review of biological markers for psychotherapy in treating depression. They found limited evidence that the benefits of psychological treatments for depression translate to biological outcomes, in that only neuroimaging markers showed promise in predicting treatment response. Two neuroimaging studies are particularly important for MODE: The Hanse-Neuro-Psychoanalysis Study investigated unmedicated outpatients with recurrent depression (n = 16) and healthy controls (n = 17) before and after 15 months of 2 or more sessions of weekly psychoanalytic psychotherapy. In the fMRI study, neural activity associated with the processing of personalized attachment material changed in patients from baseline to endpoint, but not in healthy controls. The Frankfurt fMRI/EEG Depression Study (FRED) studied a subsample of participants in the LAC Depression study (see 2.1.2, n = 24 and 24 controls) using the Operationalized Psychodynamic Diagnosis (in analogy to the Hanse-Neuro-Psychoanalysis Study) and dream words taken from a significant dream elicited in a dream interview. Measurements were obtained at three different time points, each one a minimum of 8 months apart. Results of the dream experiment revealed that dream words, in contrast to neutral words, showed a differential activation of medial orbitofrontal areas, functionally related to the self and self-agency. Results of the OPD Experiment – using the OPD-sentences collected previously – yielded similar conclusions (see Fischmann et al. [72‐75]).

MODE is a randomized, parallel, superiority and single blinded controlled trial comparing the effectiveness of two active interventions – high frequency (n = 30) vs low frequency (n = 30) psychoanalyses – in modifying brain structure and function over one year of treatment chronic depression patients who have a history of early life trauma (Fig. 1).

This study design will overcome many of the limitations of prior psychotherapy effectiveness studies. It will include an active control condition rather than a mere wait list, thereby controlling for the effects of interpersonal attention and interaction. Randomization and statistical evaluation will be performed by independent teams. Moreover, the active comparator condition, low frequency psychoanalysis, will help to control for the “allegiance” effects that confound most psychotherapy trials [85]. Finally, comparing high vs low frequency psychoanalyses will inherently provide an assessment of dose–response effects of psychoanalytic therapy on brain structure and function. Establishing dose–response associations will further improve causal inference in our study design.

Study intervention will be comprised of low frequency psychoanalytic psychotherapy (1 session a week) for early traumatized, chronically depressed patients and high frequency psychoanalytic psychotherapy (3–4 weekly sessions). The active comparator condition, low frequency psychoanalysis, delivered by study therapists who are experts in delivering both frequencies, and with the same overall manual based theoretical framework and technical interventions [86], will ensure that they will be equally aligned to both high and low frequency therapies. A group of healthy controls will be needed for brain imaging comparison purposes. A control group will allow to measure cortical thickness in patients with chronic depression in comparison to healthy control participants. Therapy sessions (45–50’ each) will be delivered in the private practice rooms or rooms of the outpatient clinics of the local psychotherapeutic institutions. Patients who will require a combination therapy of medication and psychotherapy during treatment will not be excluded but form a special subgroup that will be treated separately during data analyses. Patients who will require a change in psychotherapy setting during treatment according to patient and therapist decision will be analyzed as randomized. MODE study duration will be one year, but after 1 year of treatment initiation, treatment may continue according to patient and therapist decision. Treatments will be financed in the usual way in the participating countries (in Germany by the health insurance companies, in the US and Switzerland partly by the health insurance companies, partly by the patients themselves).

Study participants will be assessed as detailed below and in Table 3, for primary and secondary outcome measures. Patients will be assessed by independent and trained clinicians who are blind to treatment conditions.

Recruitment and treatment sites will be located in one center in the US (Los Angeles) and six centers in Europe (Germany: Frankfurt a.M., Cologne, Leipzig, Giessen, Mainz; and Switzerland: Lausanne). MRI scanning occurs in Los Angeles, Frankfurt a.M., and Lausanne. MRI data are processed in Los Angeles (CHLA). A clinical agreement has been signed and approved by each participating site.

Patients will be recruited in private psychotherapeutic and psychiatric practices, in outpatient clinics for mood disorders in hospitals. Patient flyers describing study aims and procedures will be available to potential participants with a likely diagnosis of chronic depression. Healthy controls will be recruited through informal networks. Patients with a likely diagnosis of chronic depression (BDI-II > 17) and interested healthy volunteers will be referred to the respective study center in each country and thereafter interviewed for eligibility by a research assistant.

The study will be presented to potential participants. Documents explaining the study, with its aims, procedures, benefits and risks for the participants will be provided to the participants. Interested subjects will be given a period to consider whether they would like to participate and the research team will be at their disposal to answer their eventual questions on their participation. Subjects confirming their interest in participating will then be asked to provide their informed consent to be randomly assigned to one of the treatment settings, to participate in the diagnostic, MRI, and psychometric procedures, to agree that some psychotherapy sessions are audio recorded, and agree to participate in the follow-up measurements). Participants with chronic depression and early life trauma will then be randomized in one of the two intervention groups.

The randomization procedure will consist of a computer-generated sequence of random numbers using SPSS (SPSS Statistics, version 28), which will then be used to allocate patients to either of the 2 treatment arms. The randomization sequence will be generated and maintained by an independent study administrator in Frankfurt. Once the patient is included the ID number is communicated to the study administration in Frankfurt. On the same day, the randomization arm will be communicated to the local team and applied to the participant included.

All the members of the investigating team (SCID /LIFE interviewers, MRI team etc.) will be blinded (they do neither know the treatment arm nor the names of the study therapists).

SCID interviewers will be masters-level psychologists, previously trained on administration of SCID and supervised be a senior study investigators.

In the LAC study, therapists were trained in the specific treatment technique of psychoanalysis using the Tavistock Manual [117, 118], which we have modified and extended for the MODE study [119]. The MODE manual was developed by leading clinical experts of all participating sites of the study. It integrates various psychoanalytic traditions and cultures for treating chronically depressed, traumatized patients and describes high- and low-treatments. French and English translations are available.

Both interventions will be delivered by board certified psychoanalytic therapists which have trainings and clinical experiences in low frequent and high frequent psychoanalytic therapies. Trained therapists will deliver both treatments, depending on their availability and vacancies at the time of participant enrollment. All MODE therapists are trained in the Manual [119]. Most of the study therapists in Germany have already been trained and worked in the LAC Study. Additional training will be offered for them and the new MODE study therapists of all centers in several workshops. It will include theoretical presentations, group discussion of exemplary cases, and individual case presentations. Training will be conducted by expert trainers who are qualified psychoanalysts and authors or collaborators in developing the Manual.

All study therapists will participate in monthly group supervisions or in one of the monthly “Clinical Conferences” (chairs in Germany: Marianne Leuzinger-Bohleber, Tamara Fischmann, in Lausanne: Gilles Ambresin, in SF/LA: Cheryl Goodrich), where therapists present their ongoing psychoanalyses with study patients.

A random selection of therapy sessions will be audiotaped. Adherence to the treatment protocol will be assessed by independent members of the research teams using the Comparative Psychotherapy Process Scale (CPPS; [120], see also [29]).

Power analyses using MRI measures from prior RCTs of medication therapy for the treatment of chronic depression [81, 82] indicated that a sample size of N = 30 participants for each of the 3 arms of the study would afford us a power of 80% to detect a moderate-to-large effect size (Cohen d = 0.5) with an α = 0.05 in each imaging modality (anatomical, task-based fMRI, resting state fMRI, and DTI).

Analyses will follow an intent-to-treat strategy comparing patients in the groups to which they were originally randomized.

All data will be scored and rescored by separate staff members and checked for accuracy prior to double entry into a REDCap database. Before conducting inferential statistics, we will explore data using descriptive analyses, data visualization, and examining the distributions of all imaging and clinical data. When necessary for continuous variables used as dependent variables, appropriate transformations to obtain approximate normality will be performed.

The 30 healthy controls will be used to estimate the mean and variance of brain measures in the healthy population quantify the effects of high and low frequency psychoanalysis on brain measures and to aid their interpretation as either normalizing a previously abnormal brain measure or introducing a new brain difference that attenuates symptoms.