Difficulty of Achieving Sustained Remission With Treatment-Resistant Depression

Phases in the management of a depressive episode involve acute, continuation, and maintenance treatments (Frank et al. 1991). This perspective is important when using antidepressant pharmacotherapy and psychotherapy for individuals presenting for initial treatment or for chronic depression. The usual time frame allocated for acute treatment is 6–12 weeks to achieve a response or remission of symptoms. Research studies demonstrate that continuation treatment with pharmacotherapy and/or psychotherapy for an additional several months (4–12 months) reduces the likelihood of relapse (Dobson et al. 2008; Dunner 2001; Gelenberg et al. 2003; Keller et al. 2000, 2007a, 2007b; Klein et al. 2004; Kocsis et al. 2003; Paykel et al. 1995). Maintenance treatment is the next step (i.e., beyond 4–12 months), and evidence supports the efficacy of maintenance treatment for individuals with recurrent and chronic forms of depression (Frank et al. 1990; Keller et al. 2007a; Klein et al. 2004).

Research studies demonstrate that individuals with chronic forms of depression are more difficult to treat than individuals with acute depressive episodes (Dunner 2001). Furthermore, the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study showed a decrease in the rate of antidepressant response with repeated treatment failures (Gaynes et al. 2009; Rush et al. 2006). For example, individuals who experience three failed treatment trials have a low (about 15%) rate of remission in the subsequent trial. These data are similar to the results of a 2-year study of “treatment as usual” for individuals who had experienced multiple failed antidepressant treatments (Dunner et al. 2006; George et al. 2005).

Although most depressed patients respond well to treatment with psychotherapy and/or antidepressant pharmacotherapy, those who do not respond can be considered to have treatment-resistant depression (TRD). Sustained remission for patients with TRD is difficult to achieve with currently available options. A patient who attains remission after one prior antidepressant treatment failure has a 40% chance of relapse over the next year, whereas a patient who has attained remission after three prior antidepressant treatment failures has a 65% chance of relapse (Warden et al. 2007). Table 6–1 displays data from the STAR*D study and shows how increasing treatment resistance predicts an increasing chance of relapse. When patients do not respond to multiple medications, their prognosis for long-term remission decreases. One might say the “durability of response” to antidepressant medications decreases with more failed trials.

Durability of Antidepressant Response After Acute TMS

Once a patient responds to TMS, how long will the benefit last? Most patients pose this question during the consent process because they have experienced the disappointment of initially benefiting from an antidepressant treatment only to have their symptoms recur in the ensuing months. To investigate the mean remission time and the predictors associated with the treatment’s duration, Cohen et al. (2009) performed a large retrospective, naturalistic study with 204 patients who underwent TMS therapy. Patients were followed for up to 6 months after acute treatment, and about 80% took psychotropic medications. The rate of event-free remission, with the end point defined as relapse (i.e., Hamilton Depression Rating Scale [HDRS] scores higher than 8), was 75.3% at 2 months, 60.0% at 3 months, 42.7% at 4 months, and 22.6% at 6 months. The mean duration of remission was approximately 4 months (119 days), with younger age and greater number of TMS sessions predicting greater durability of benefit.

Janicak et al. (2010) studied the durability of TMS in a population of 99 patients with major depressive disorder who had at least partially responded to acute TMS treatment while medication free. The patients then received antidepressant monotherapy for 24 weeks. If patients met predefined criteria for symptom worsening, they could receive TMS reintroduction (i.e., two sessions/week for 2 weeks and, if needed, five sessions/week for 4 additional weeks). Thirty-eight patients (38%) had symptom worsening and received TMS reintroduction. Thirty-two of the 38 patients (84%) benefited, with the mean time to reintroduction of TMS being 109 days and the mean number of TMS reintroduction sessions being 14.3. Fifteen patients needed more than one course of TMS, and five patients needed up to three courses. Ten patients relapsed despite access to flexible reintroduction of TMS. TMS was found to be a durable and safe treatment when patients were allowed “flexible reintroduction of TMS” combined with antidepressant monotherapy, and those who initially achieved remission had a better prognosis.

Dunner et al. (2014) reported the 1-year outcome in 257 patients with major depressive disorder treated with TMS. The acute treatment response was reported by Carpenter et al. (2012). Because this was an observational study conducted across 42 clinical practices in the United States, all patients were permitted clinician-directed treatment as usual (i.e., patients were not limited to a predefined single antidepressant as in the Janicak et al. [2010] study). Most were treated with antidepressant medications, and many received other medications (e.g., second-generation antipsychotic augmentation) during the acute and follow-up periods. Patients were allowed TMS reintroduction after acute treatment if deemed appropriate and prescribed by their physician. Other treatments such as psychotherapy were not reported. Over 60% of patients who had responded to or achieved remission during acute treatment with TMS sustained their response for 1 year. Ninety-three patients were treated with TMS during the ensuing 12 months of follow-up; the mean number of TMS sessions for this group was 16.2. Of the 45 subjects who did not maintain their remission or response status, 31 relapsed within 6 months. No safety or tolerability issues were noted during reintroduction of TMS.

These studies indicate that acute TMS therapy is beneficial for most patients with more chronic forms of depression for up to 4 months. Although research studies of TMS involved antidepressant medication–free patients, in clinical practice most patients continue medication after the acute phase and do not reduce their medication loads (Carpenter et al. 2012; Dunner et al. 2014). Having access to flexible doses of TMS to treat recurrent symptoms during the continuation phase improves durability, and most patients with such access require fewer TMS sessions to maintain their remission or response status. Continuing medication and reintroducing TMS is effective, but more research is needed to determine whether it is the optimal strategy for keeping patients well. For example, head-to-head studies comparing different protocols are needed, and researchers need to clarify whether participants are allowed to simultaneously receive other treatments with TMS.

Following TMS treatment, patients should be closely monitored, and their symptoms should be measured with a validated depression questionnaire. Research is needed to try to determine which patients are at most risk for relapse. Perhaps certain clinical or demographic variables predict relapse after TMS therapy. Several candidate variables were examined in the studies described in this section, but the results are inconsistent. Overall, patients who achieve remission with acute TMS have the best prognosis for maintaining response.