This article reviews what is new in major depressive disorder: from clinical trials and research, through to the clinic
Emmanuel Augeraud MD
Psychiatrist and addictions expert
CHP – 29, avenue du Général Leclerc – 64039 Pau Cedex
EPSM Lille-Métropole – BP 10 – 59487 Armentières cedex, France
Email: [email protected]
The screening and management of major depressive syndromes are significant challenges for public health. Such syndromes affect 150 million people worldwide, and are the second cause of disabling health conditions.1
Depression impairs the normal daily functioning of sufferers as well as their quality of personal and socio-professional life (by 2020, according to the World Health Organization, it will be the second biggest illness in terms of global costs after cardiovascular disease).2
It also has serious consequences for sufferers regarding the risk of suicide, which is 20 times higher among depression sufferers than among the general population. Depression is thought to be the main cause of suicide.3
In France, the annual prevalence (of depressive disorders) is about 9% (5–15% depending on the publication) and the annual cost is thought to be around €1 billion per year, although this figure is likely to be an underestimate.4 Almost half of those with depression do not seek medical help and general practitioners give the majority of diagnoses. This means that only 5% of suffers actually receive appropriate medical care for their condition.
This article looks at the latest progress in chemotherapy for unipolar depression. Five different aspects are covered are: the assessment, drug therapy, including those for treatment-resistant depression (TRD), antidepressants being developed, and non-drug therapies.
Assessing unipolar depression
Effective treatment requires an effective assessment, which is a continuous process.
Assessment of the syndrome
Depressive syndrome is defined by the international classifications5–6 as a set of symptoms combining (to a greater or lesser extent):
- Pervasive or persistent low mood.
- A lack of energy or increased fatigue.
- A loss of self-confidence or self-esteem, unfounded feelings of excessive or inappropriate guilt.
- Thoughts of death or recurrent suicidal ideas or suicidal behaviour of any type.
- A decrease in the capacity to think or concentrate.
- Changes in psychomotor activity, characterised by agitation, or lethargy (reported or observed).
- Sleep disorders of any kind.
- A change in appetite (decrease or increase) with the related consequences on bodyweight.
These symptoms must have been present over the same period of at least two weeks, marked a behavioral change compared with previous functioning and cause suffering to the individual or have a marked impact on the ability to function in different aspects of the sufferer’s life (professional, social, or other).
Depression is considered as light to moderate for patients displaying between five and seven of the aforementioned symptoms and severe when eight or more are present. At least one of the first two symptoms mentioned previously is required for diagnosis.
Depression is referred to as unipolar in the absence of hypomanic or manic symptoms that correspond to the criteria for a manic or hypomanic episode at any given time in the person’s life. Finally, depression is a classified as a disorder when the episode cannot be attributed to the use of a psychoactive substance or to an organic disorder.
The concomitant assessment and management of comorbidity is important. Depression is an isolated pathology in only 26% of cases. The most frequent comorbidities7 are social phobias (27.1%), specific phobias (24.3%) and dependency on psychoactive substances (24%).
Evaluation of treatment
There are numerous validated, recognised evaluation scales and tools that contribute to a self-assessment or hetero-evaluation of the severity of the depressive episode, to appraise the monitoring process, the response to treatments and the remission and recovery periods or simply the sufferer’s quality of life. During remission, they are also used to evaluate the persistence of residual symptoms and therefore contribute to appraising the long-term prognosis. However, they are not sufficient in themselves to diagnose a major depressive episode.
Clinical remission is related to an improvement in the scores on rating scales such as the HDRS (Hamilton depression rating scale) and the MADRS (Montgomery–Åsberg depression rating scale) but the sufferer’s quality of life compared with their previous state, their recovery objective and their personal socio-professional goals must also be considered. The sufferer can be evaluated using the Zimmerman’s remission from depression questionnaire (RDQ).8 Clinical symptoms of depression and functional impairment are closely related. In some patients, signs of depression may first appear in the workplace, including conflict with other workers, poor motivation, increased errors, and reduced task vigilance. These mood, thought, cognitive and physical complaints can be linked to the clinical symptoms of depression that are typically the foundation for making a formal diagnosis.
There can be cultural differences in how patients describe their symptoms of depression, with some more likely to report cognitive complaints and others more focused on affective symptoms.
When performing a psychiatric assessment, it is important for family doctors to consider both the symptoms of the disorder and their impact on functional outcomes, and to document their findings in the patient’s chart. This is what the RDQ is used for.
A consensus is emerging on the treatment objectives of a major depressive episode (MDE):
– Obtain clinical remission of the MDE using antidepressants.
– Adopt a long-term perspective. Relapses are the main risk factor in the medium- to long-term. Treatment for depression must therefore include functional recovery, in social, emotional and professional terms.
Antidepressant drug therapy
The effect of antidepressants is not expected until two to three weeks after the start of treatment; this is the time required for the physiological effect of the medication to act on the neurotransmitters. Six weeks must be allowed to pass however before questioning the effectiveness of the treatment.
The course of treatment must continue over several months (six to eight months, or even a year), a phase that serves to consolidate the result and prevent any relapse that might jeopardise the development of the illness. Certain patients may need to continue the treatment over several years (maintenance) to avoid frequent relapses.
Stopping treatment before the end of the recommended duration exposes the sufferer to a higher risk of recovery failure in the medium- to long-term. The medication must be stopped in agreement with the physician, and the doses gradually decreased, usually over a few weeks.
All the therapeutic classes have demonstrated their effectiveness in the treatment of a depressive episode.9 The most commonly used in the first-line treatment of depression are the SSRIs (selective serotonin reuptake inhibitors).
The choice of antidepressant should preferably be based on certain specific criteria:
- The therapeutic use of side effects (for example, seeking stimulation obtained through the prescription of fluoxetine), or for sleep disorders such as insomnia, for which the prescription of an antidepressant with a hypnotic, sedative action would be preferable, such as mianserin or mirtazapine, or perhaps even agomelatine.
- The preferential indication of a therapeutic class in certain psychiatric comorbidities, for example, SSRIs for obsessive disorders.
- The respect of contraindications (organic comorbidities) and the risk of medicinal interactions (cytochrome P450).
The definition of TRD. It effectively corresponds to a persistent depressive episode after one or more well-conducted courses of treatment using antidepressants.
Only one third of patients treated respond correctly to the first monotherapy prescribed. TRD represents over 30% of the global cost of depression. The STAR-D study9 revealed a resistance level of 33% after four stages of treatment.
Studies have shown the beneficial effect of adding an atypical antipsychotic such as olanzapine or quetiapine to SSRIs/SNRIs (serotonin-norepinephrine reuptake inhibitors), compared with standard monotherapies involving only serotoninergic agents.10 The co-prescription of fluoxetine/olanzapine is also approved. However, studies show one benefit, which is relatively small compared with other strategies for treating resistant depression, by adding lithium, T3 thyroid hormones, or folate.11
Other configurations are currently being studied, such as adding buspirone11 or adding dopaminergic agents to a serotoninergic monotherapy.12
Antidepressants under development
These combine multiple modes of monoaminergic action. Preclinical tests have shown that vortioxetine13 for example, has the effect of increasing the concentrations of five monoaminergic neurotransmitters: serotonin, noradrenaline, dopamine, histamine and acetylcholine.
This phenomenon is likely to have a direct relation to the improvement of depressive symptoms, and is also thought to improve response times to treatment and increase remission rates.
Beyond monoamine neurotransmitters
Brain studies among patients suffering from depression revealed an abnormal neuronal plasticity and an excessive secretion of glutamate, both of which were improved by current monoaminergic antidepressants.14
Other molecules that regulate the secretion of glutamate and act on synaptic plasticity are being studied in the treatment of depression. Examples include memantine15 and ketamine.16
(1) Electroconvulsive therapy (ECT): ECT is currently the best treatment for TRD in terms of response rate (80–90%) and remission.17 It is indicated as a first-line treatment in severe cases of melancholic depression, and as a second-line therapy after a well-conducted but ineffective medicinal therapy.
The therapeutic response can sometimes occur after a few sessions of treatment and no study has proven the need to prescribe any specific medicinal therapy to sustain the therapeutic response after ECT treatment.
(2) Transcranial magnetic stimulation: This is a therapeutic alternative in the treatment of low to medium treatment-resistant depression and after the failure of a therapy included in a clinical test.
Meta-analyses are said to have shown lower benefits than for ECT.18
(3) Others: Other non-medicinal treatments are still scarcely used, or under study and their effects and benefits are subjects of controversy, such as deep brain stimulation (DBS), transcranial direct current stimulation (tDCS), vagus nerve stimulation (VNS), light therapy or a sleep cure. Physical exercise is also thought to have an antidepressant action regardless of the frequency or intensity of the effort, but the improvements are relatively insignificant according to the latest meta-analyses.19
Psychotherapies are indicated only in mild cases of depression and in association with a course of antidepressants in moderate intensity cases.20
Cognitive and cognitive–behavioural therapies, support psychotherapies and interpersonal or family psychotherapies have been the subject of controlled studies in cases of mild to moderate intensity depression. Psychoanalytic psychotherapies, which are best used well after the acute phase, are a useful solution for certain patients.
Finally, mindfulness-based cognitive therapy has been shown to reduce the risk of relapse or recurrence in depression sufferers compared with routine care programmes.21
Depression is the most common psychiatric illness in the world and is therefore a major public health issue. Its cost and impact on society are significant, and yet this pathology is still insufficiently diagnosed. Studies show that the medical management of depression is inappropriate in the majority of cases.
A consensus on the objectives of the treatment of an MDE is emerging: to obtain clinical remission by targeting the disappearance of residual symptoms to prevent relapse and depressive recurrences. An important aspect is to improve the patient’s quality of life, which supposes their mental wellbeing and the recovery of their former functional state.
Neuroleptics also have a place of growing importance in the treatment of TRD, and lithium and thyroid hormones can also be included in therapeutic strategies. bupropion, ketamine, and many others are currently being tested.
In addition to chemotherapy, other non-drug therapies, including surgical therapies, may be used in complement to one another in the management and treatment of depressive episodes. These include psychotherapy, ECT, DBS or TMS.
In all cases, the treatment and management of depression requires close collaboration between sufferers and carers, a configuration termed the “therapeutic alliance”, which is the foundation for determining the care and treatment project. The programme is defined considering patients’ wishes, and they are informed of the nature of their disorders, their development, management possibilities, the frequency of consultations, and the importance and mechanism of action of the medical treatment. The role of the family circle must not be underestimated, in the sense that it can help protect sufferers who have lost their self-confidence.
- Once an accurate diagnosis of unipolar depression is made, clinicians must monitor symptoms, functioning, and quality of life to determine if treatment is effective.
- Treatment of unipolar depression may be subject to guidelines.
- Addressing inadequate response in patients with major depressive disorder helps avoiding resistance.
- Some of the novel antidepressants in development target imppaired monoaminergic neurotransmission. Additionally, a number of novel agents in development target components of the neuroplasticity hypothesis of depression including hypothetically overactive glutamatergic neurotransmission.
- Among non-pharmacological approaches for major depressive disorder, ECT remains the best treatment and neurostimulation therapies hold promise.
- Ferrari AJ et al. Burden of depressive disorders by country, sex, age, and year: Findings from the global burden of disease study 2010. PLoS Med 2013;10(11):e1001547.
- Mental Health Basics. July 2011. Center for Disease Control and Prevention, Atlanta, GA. www.cdc.gov/mentalhealth/basics.htm.
- Harris EC, Barraclough B. Suicide as an outcome for mental disorders. A meta-analysis. Br J Psychiatry 1997;170:205–28.
- Kleine-Budde K et al. The cost of depression – a cost analysis from a large database. J Affect Dis 2013;147(1–3):137–43.
- World Health Organization. The ICD–10 classification of mental and behavioural disorders: clinical descriptions and diagnostic guidelines. Geneva, 1992.
- American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA, American Psychiatric Association, 2013.
- Wittchen H-U, Essau CA. Comorbidity and mixed anxiety depressive disorders: Is there epidemiologic evidence? J Clin Psychiatry 1993;54(Suppl 1):9–15.
- Zimmerman M et al. A new type of scale for determining remission from depression: the remission from depression questionnaire. J Psychiatr Res 2013;47(1):78–82.
- Sinyor M, Schaffer A, Levitt A. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Trial: A review. Canadian J Psychiatry 2010;55(3):126–35.
- Citrome L. Adjunctive aripiprazole, olanzapine, or quetiapine for major depressive disorder: an analysis of number needed to treat, number needed to harm, and likelihood to be helped or harmed. Postgrad Med 2010;122(4):39–48.
- Connolly KR, Thase ME. Emerging drugs for major depressive disorder. Expert Opin Emerg Drugs 2012;17(1):105–26.
- Goss AJ et al. Modafinil augmentation therapy in unipolar and bipolar depression: a systematic review and meta-analysis of randomized controlled trials. J Clin Psychiatry 2013;74(11):1101–7.
- Katona CL, Katona CP. New generation multi-modal antidepressants: focus on vortioxetine for major depressive disorder. Neuropsychiatr Dis Treat 2014;10:349–54.
- Duman RS, Aghajanian GK. Synaptic dysfunction in depression: potential therapeutic targets. Science 2012;338:68–72.
- Machado-Vieira R et al. Novel glutamatergic agents for major depressive disorder and bipolar disorder. Pharmacol Biochem Be 2012;100:678–87.
- McGirr A et al. A systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials of ketamine in the rapid treatment of major depressive episodes. Psychol Med 2015;45(4):693–704.
- Sackeim HA et al. Effect of concomitant pharmacotherapy on electroconvulsive therapy outcomes: short-term efficacy and adverse effects. Arch Gen Psychiatry 2009;66(7):729–37.
- Berlim MT et al. Response, remission and drop-out rates following high-frequency repetitive transcranial magnetic stimulation (rTMS) for treating major depression: a systematic review and meta-analysis of randomized, double-blind and sham-controlled trials. Psychol Med 2014;44(2):225–39.
- Rethorst CD, Wipfli BM, Landers DM. The antidepressive effects of exercise: a meta-analysis of randomized trials. Sports Med 2009;39(6):491–511.
- Cuijpers P et al. The efficacy of psychotherapy and pharmacotherapy in treating depressive and anxiety disorders: a meta-analysis of direct comparisons. World Psychiatry 2013;12:137–48.
- Kuyken W et al. Effectiveness and cost-effectiveness of mindfulness-based cognitive therapy compared with maintenance antidepressant treatment in the prevention of depressive relapse or recurrence (PREVENT): a randomized controlled trial. Lancet 2015 Apr 20. pii: S0140-6736(14)62222-4. doi: 10.1016/S0140-6736(14)62222-4. [Epub ahead of print].