Persistent depressive disorder

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Persistent depressive disorder, in its various forms, is common among clinical and community populations. Patients with chronic forms of depression may respond to psychotherapy, pharmacotherapy, or a combination of both. However, patients with chronic forms of depression require a longer treatment period, more psychotherapy sessions, and/or higher doses of antidepressant medication than do patients with acute forms of depression.[42] A meta-analysis found that pharmacotherapy may be more effective than psychotherapy in the treatment of dysthymic disorder.[43] Education about the disorder and the treatment is important in order to gain compliance and achieve better outcomes.

Only a few psychotherapies have been studied for the treatment of patients with dysthymia and chronic major depression. [ ] [ ] These include cognitive behavioural therapy (CBT), interpersonal therapy (IPT), and cognitive behavioural analysis system of psychotherapy (CBASP). In general, empirically supported psychotherapies have been comparable to antidepressant medication in depression, though rarely studied specifically in persistent depressive disorder.[44]

It is likely that any antidepressant medication would be effective for treatment of persistent depressive disorder, and classes studied include tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), selective serotonin-reuptake inhibitors (SSRIs), serotonin-norepinephrine-reuptake inhibitors (SNRIs), and atypical agents such as the antipsychotic ritanserin. Some agents have not yet been evaluated in randomised and placebo-controlled studies. The choice of antidepressant is the same for more acute forms, the clinician may be best guided by patient characteristics, starting with the generally safer SSRIs where possible.

One study demonstrated the effect of combined pharmacotherapy-psychotherapy. This was conducted in patients with chronic major depressive disorder. The study showed that CBASP and antidepressant medication (nefazodone) had a better acute (12 week) outcome than psychotherapy or medication monotherapy.[42]

Other considerations

A study of collaborative care in elderly people with depression reported a similar rate of initial response comparing 'young old' with 'old old' patients, but long-term response and remission were poorer among the 'old old'.[45] Patients with dysthymic disorder were not studied separately from those with other forms of depression.[45] Benefits persisted at 24-months follow-up, and continued after additional resources were withdrawn.[46] A Cochrane review looking at collaborative (shared) care for a number of long-term conditions, both medical and psychiatric, found that shared care improved outcomes and recovery rates in patients with long-term depression. The review also found a modest improvement in mean depression scores for patients treated using a "stepped care" model of service delivery (where patients are offered the most effective but least resource intensive treatments first, only ‘stepping up’ to more resource intensive/specialist services as required). Again, patients with dysthymic disorder were not studied separately from those with other forms of depression.[47]

Motivational interviewing and culturally sensitive treatment approaches may help engage patients from minority backgrounds who have depression.[48]

There are limited data regarding psychotherapy effects on persistent depressive disorder in children. However, studies in adolescents provide data for the effectiveness of group intervention programmes in the prevention of depression and/or persistent depressive disorder among high-risk adolescents.[49][50] Cognitive behavioural therapy (CBT) and interpersonal therapy are both recommended options to consider for children and adolescents with persistent depressive disorder, according to American Academy of Child and Adolescent Psychiatry practice guidelines.[41] Among adolescents with major depressive disorder and/or persistent depressive disorder, there is weak evidence to suggest that CBT improves self-reported depressive symptoms and clinician-reported functional impairment, according to one systematic review.[51] Other meta-analyses report mixed benefits of CBT in children and adolescents with major depressive disorder and/or persistent depressive disorder; in subgroup analyses, statistically significant improvements in symptoms were found for CBT versus wait-list and ‘named control group’ but not for CBT versus ‘psychological placebo’ or treatment as usual.[41][52][53] There is also weak evidence in favour of interpersonal therapy among children and adolescents with major depressive disorder and/or persistent depressive disorder.[51][52][53][54] The American Academy of Pediatrics has issued guidelines for identification of adolescents with depression in primary care and referral to appropriate evidence-based treatment.[39][55]

Many patients with persistent depressive disorder have comorbid medical conditions such as cardiovascular disease. The impact of antidepressant treatment combined with psychotherapy in collaborative care on cardiac mortality has been studied with mixed results.[56][57][58] A study of depressed primary care patients 60 years of age and older (87% of whom were chronically depressed) suggests cardiac-protective effects of collaborative care prior to clinical cardiovascular disease onset, with fewer significant cardiovascular events over an 8-year follow-up.[59]

Psychotherapy

CBT, IPT, and CBASP have been studied and shown to be effective in the treatment of patients with the dysthymia subtype of persistent depressive disorder. Other psychotherapies may or may not be of benefit but have not been specifically studied in patients with persistent depressive disorder.

A review of systematic reviews looking at a number of different pharmacological and non-pharmacological treatments for major depression found that, of the non-pharmacological treatment options, CBT has the best strength of evidence comparable to second generation antidepressants (e.g., selective serotonin reuptake inhibitors or selective serotonin-noradrenaline reuptake inhibitors).[60] Although this review excluded patients with dysthymia, it is likely that some of the studies within the review would have included patients with double depression. Therefore, it is reasonable to conclude that of the non-pharmacological options for persistent depressive disorder, CBT might be useful to try in patients with persistent depressive disorder as a first option when medications are ineffective or not tolerated. Treatment of patients with persistent depressive disorder with CBT requires more treatment sessions than does treatment of patients with acute forms of depression. CBT was less effective than fluoxetine in one study.[61]

CBASP is a psychotherapy that was developed for the treatment of patients with chronic forms of depression. It has also been shown to be effective for patients with persistent depressive disorder.[62] However, CBASP is not widely available. CBASP was effective alone and when combined with the antidepressant in a study of patients with chronic major depression.[42] A replication study of a similar methodology, the REVAMP study, did not find additional benefit for CBASP versus medication alone.[63]

IPT has also shown to be effective for patients with dysthymia.[44][64][65] However, a trial of 94 patients with 'pure' dysthymic disorder subtype of persistent depressive disorder (e.g., without comorbid major depressive disorder) who were treated for 16 weeks with either IPT, brief supportive psychotherapy (BSP), sertraline, or sertraline plus IPT found response rates of 58% for sertraline alone; 57% for sertraline plus IPT; 35% for IPT; and 31% for BSP.[66] Methodological difficulties, including small sample sizes, may have limited differential outcome findings, but the authors concluded that pharmacotherapy alone may provide more acute benefits than psychotherapy alone. A meta-analysis in older adults determined that cognitive behavioural therapy is effective for various forms of depression (major and minor depression and dysthymia), but was not able to demonstrate superiority to pharmacotherapy or other forms of psychotherapy.[67]

One meta-analysis found that various forms of psychotherapy, including face-to-face CBT, problem-solving therapy, and interpersonal psychotherapy, as well as remote therapist-led CBT and problem-solving therapy were effective in depressed primary care patients; however, with evidence for less effect among dysthymic patients than those with major depression.[68]

Pharmacotherapy

Antidepressants from various classes have been reported to be effective for the treatment of patients with various forms of persistent depressive disorder including dysthymia and chronic major depression. Given the 2013 change to the previous DSM-IV categorisation of persistent depressive disorder, most existing studies are not for this particular classification and have included either patients with dysthymia or with chronic major depression.

Choice of antidepressant is the same as for more acute forms of depression. Typically, an SSRI is started, and then if the first medication is not tolerated or effective, it may be beneficial to switch to an antidepressant of another class: for example, bupropion (sustained- or extended-release),[69] an SNRI, or vortioxetine (a bimodal oral antidepressant that is thought to work through a combination of reuptake inhibition of serotonin and modulation of serotonin receptor activity). Subsequent options include combination pharmacotherapy.

The key to treatment is to give relatively high doses for relatively long periods of time (compared with treatment of acute forms of depression).

Studies have demonstrated that a wide range of medications are effective for the dysthymic subtype of persistent depressive disorder and for chronic major depression, although in the US there are not yet any medications with an FDA-approved indication for this condition. The placebo response rate is low in dysthymic disorder and chronic major depression, and the medication response rate, though perhaps lower than seen in acute major depressive disorder (MDD), is reproducibly higher than the placebo response rate.

Medication is significantly more effective than placebo in nearly all double-blind controlled studies of dysthymia.[70][71][72] One meta-analysis found that remission was greater with SSRIs and TCAs than with placebo, with comparable efficacy of SSRIs and TCAs, but with greater rates of adverse effects and discontinuation in patients taking TCAs as opposed to SSRIs.[71] A network meta-analysis found that a number of different antidepressants (including fluoxetine, paroxetine, sertraline, moclobemide, imipramine, and amisulpride) were superior to placebo for treatment of persistent depressive disorder.[72] Pairwise comparison showed that moclobemide and amisulpride may have advantages over fluoxetine.[73]

Persistent depressive disorder includes various forms of chronic depression, and any pharmacotherapy shown to be useful for depression is likely to work for PDD. 'Double depression' (dysthymia complicated by major depressive episode) is treated like a major depressive disorder episode. Comparing trials of patients with dysthymia and patients with MDD, placebo response rates in dysthymic disorder have been shown to be significantly lower than those found for MDD (29.9% versus 37.9%, P=0.042), and number needed to treat (NNT) for dysthymic disorder was 4.4 compared with 6.1 for MDD, which was not statistically significant. Results from further meta-regression analysis of data have suggested a greater relative risk for response with dysthymia than with MDD.

One large, randomised, double-blind, placebo-controlled trial in people with dysthmyia without concurrent major depression showed positive effects at 12 weeks of treatment for sertraline and imipramine versus placebo.[74] This study was longer in duration than the usual studies of acute major depression and used relatively high doses.

A study of fluoxetine versus placebo in geriatric patients with dysthymia showed 'limited effects' for fluoxetine after 12 weeks of treatment.[75] In contrast, in younger adults fluoxetine was more effective than placebo.[76] A small study in elderly patients with 'pure' dysthymia (no comorbid major depression) found paroxetine was more effective than placebo in improving symptoms and quality of life and was generally well-tolerated.[77]

Other studies have tended to be open-label with small sample sizes and non-comparative clinical trials. These studies have shown positive results for venlafaxine, mirtazapine, citalopram, and bupropion sustained-release, and negative results for fluvoxamine.[69][78][79][80][81] [ ] [ ] The atypical antipsychotic medication ritanserin in low doses has shown benefit in dysthymic disorder.[82] We are aware of no studies of newer agents (such as vortioxetine, vilazodone, and levomilnacipran) in PDD.

There are limited data regarding treating children, but children and adolescents with depression should be systematically screened, assessed for suicide risk, and provided appropriate treatment referrals with evidence-based treatment if available.[39][55] The usual caveats considering antidepressants and an increase in suicidal thinking in young patients should be followed.[83][84] Patients should be monitored closely for changes in behaviour and/or the emergence of suicidal thinking. Family members must be made aware that such changes can occur during treatment, and should contact the prescriber if need be. Fluoxetine is approved in some countries for use in children with depression (for children aged 8 years and over). [ ]

See Depression in children.

Most patients with persistent depressive disorder have comorbid psychiatric conditions, such as anxiety disorders and substance misuse. Response rates are similar among alcohol misusers and patients who do not misuse alcohol,[85] and a similar antidepressant response is seen among patients with and without opiate-use disorders.[86] Among marijuana users with either major depressive disorder or dysthymia, venlafaxine was associated with an increase in marijuana use, and no improvement in depressive symptoms when compared with placebo.[87] Among cocaine users with major depression or dysthymia, venlafaxine treatment did not improve mood or cocaine use outcomes.[88] If the patient has significant alcohol misuse, non-SSRI antidepressants, such as TCAs, may be more effective than SSRI antidepressants.[85] If the patient has significant insomnia, using a sedating antidepressant might be a better choice than an antidepressant that causes more insomnia. Some patients with persistent depressive disorder have comorbid attention deficit disorder, and may benefit from adjunctive stimulant medication. Among patients with comorbid fibromyalgia, pregabalin may provide benefit for pain as well as mood and anxiety symptoms.[89]

Meta-analyses suggest that antidepressant pharmacotherapy may be more effective than psychotherapy for the treatment of patients with the dysthymic subtype of persistent depressive disorder.[70][90][91][92] However, pharmacotherapy was shown not to be more effective than placebo in individuals with physical illness complicating depression.[93] There was insufficient evidence to recommend one second-generation antidepressant over another.[94][95] Data from a systematic review to determine whether particular patient characteristics could predict the outcome of specific treatment, medication, or psychotherapy alone, or combined treatment, suggest that medication is probably the best treatment for dysthymia and that combined treatments are effective in depressed outpatients as well as in depressed older adults, but the number of studies comparing combined treatments is only about 20% of the number needed to make such determinations.[96] An analysis of one randomised control trial suggests that early childhood trauma (for example sexual abuse or the early loss of a parent) may be associated with better outcomes with psychotherapy as opposed to antidepressants.[97]

In adults, continuation treatment for persistent depressive disorder including psychotherapy, pharmacotherapy, or combined treatments may be helpful, but there is limited evidence due to small numbers of high quality studies.[98] [ ] A review of continuation antidepressant treatment in children and adolescents with major depression or dysthymia showed lower rates of relapse with active medication treatment compared with placebo, though the number and quality of studies is limited.[99]

Other treatments

Exercise has been studied as a treatment for depression, though not specifically for persistent depressive disorder, and results suggest benefit in some patients comparable to medication.[100] [ ] In one study, regular exercise produced frequent sustained remission at 1-year follow-up.[101] Exercise may have beneficial effects on neurotrophic factors such as brain-derived neurotrophic factor (BDNF) in people diagnosed with depression.[102] A small study showed that body psychotherapy in patients with chronic depression, including exercises, movement strategies, and sensory awareness procedures, led to improved depressive symptoms compared with a waiting-list control.[103] Data on lifestyle modification, including adoption of Mediterranean diet and increased exercise, have shown benefit for depressive symptoms and disorders.[104] One study suggested that yoga might be effective in some patients with depression, although the authors stated that further studies were needed.[105] Low-quality evidence suggests acupuncture may reduce the severity of depression compared to no treatment, wait list, treatment as usual, or control acupuncture; however, there is no clear evidence regarding the risk of adverse events or comparisons to other treatments like medication or psychotherapy.[106] [ ] Internet-based therapies have been shown to be effective for treatment of depression, including some studies including individuals with persistent depressive disorder.[107]

Work impairment is common among individuals with various forms of depression, including persistent depressive disorder. One Cochrane review of interventions for depressed workers (with major depression or high levels of depressive symptoms) concluded that there is moderate quality evidence that adding a work-directed intervention to a clinical intervention reduces days on sick leave compared with a clinical intervention alone. In addition, enhancing primary or occupational care with cognitive behavioural therapy appears to reduce sick leave compared with usual care. Sickness absence is also reduced by structured telephone outreach and a care management programme that includes medication. However, research is limited and more studies are needed on improving work functioning in patients with depression.[108]

Pregnancy

In obstetrics/gynaecology settings, collaborative care may be helpful in engaging women with depression, many of whom have PDD.[109] Clinicians should carefully discuss the risks of remaining on antidepressant treatment during pregnancy, against the risks of stopping or avoiding antidepressants and exposing the fetus to the harmful effects of depression.

See Depression in adults.

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