Disease overview – Major depressive disorder
R. Hamish McAllister-Williams PhD MD FRCPsych
Reader in Clinical Psychopharmacology and Honorary Consultant Psychiatrist, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK
Introduction
Major Depressive Disorder (MDD) is a terminal, though treatable, illness. Even in the absence of mortality, MDD has a huge negative impact on quality of life and productivity.
MDD costs the UK economy over ￡9 billion per year in direct and indirect costs.
Epidemiology
MDD is extremely common and highly recurrent with as many as 80% of individuals who experience one episode having a recurrence. MDD frequently presents with comorbid physical or psychiatric complaints.
Diagnosis
There is clear evidence of altered or abnormal biology in those suffering from MDD. Criteria such as the International Classification of Disease version 10 (ICD-10) and the Diagnostic and Statistical Manual version IV (DSM-IV) do serve to help improve the reliability of a diagnosis of MDD.
Pathophysiology
From a biological perspective the most prominent hypotheses around MDD over the last five decades have related to abnormalities of serotonergic (5-HT) and noradrenergic neurotransmission. What is clear is that MDD is NOT simply due to low levels of5-HT and/or noradrenaline as originally suggested.
Management
Many guidelines exist for the management of MDD including those produced by NICE and the BAP. Early identification and treatment is important. Management strategies fall into psychosocial and physical modalities.
Choice of antidepressant
The choice of antidepressant is based on factors other than potency. The relative side-effect burden together with the presence of concurrent illnesses and additional medication, need to be considered.
Tricyclic antidepressants (TCAs)
TCAs are usually associated with a greater burden of side-effects than many of the newer antidepressants such as the SSRIs. TCAs – with the exception of lofepramine, which is generally better tolerated and less toxic than other TCAs – are not appropriate first-line treatments in patients and should generally not be used in primary care.
Selective serotonin reuptake inhibitors (SSRIs)
SSRIs tend to be better tolerated than TCAs and are recommended by NICE as first-line treatments in primary care. Increased anxiety and agitation when starting SSRIs may lead to an increased suicide risk and so close monitoring is necessary in the early stages of treatment. The most prevalent side-effect of SSRIs is sexual dysfunction, with decreased drive and arousal plus difficulty reaching orgasm. This is associated with reduced compliance.
Monoamine oxidase inhibitors (MAOIs)
Traditional MAOIs have little role as first- or second-line treatments, owing to their interactions with various drugs and foods.
Serotonin and noradrenaline reuptake inhibitors (SNRIs)
Venlafaxine has poorer tolerability compared to SSRIs and has a high risk of discontinuation symptoms (similar to paroxetine). The only monitoring requirement is that blood pressure should be measured especially when doses of 225 mg or more are used.
It remains unclear if duloxetine has the same advantages over SSRIs that venlafaxine has.
As a result, whilst included within treatment options generally, it is not bracketed with venlafaxine, amitriptyline and escitalopram for more severely ill patients by the BAP.
Other antidepressants
Reboxetine is a selective noradrenaline reuptake inhibitor. It appears to be relatively well tolerated but evidence about its effectiveness raises questions regarding its potency.
Mirtazapine is an α2-adrenoceptor antagonist and is also a sedative. It appears to be well tolerated early on by patients because it improves sleep and reduces anxiety symptoms. However, its main drawback is that it can lead to significant weight gain. One major advantage of mirtazapine is that it is associated with a lower rate of sexual dysfunction than most other antidepressants including TCAs and SSRIs.
Agomelatine is an antidepressant that is a combined melatonin agonist and 5-HT2c receptor antagonist. It seems to have at least comparable efficacy compared to other antidepressants as well as being very well tolerated (including lack of side effects of weight gain and sexual dysfunction). Liver function test monitoring is required. It appears that it would be of particular use in patients in whom one would wish to avoid the side-effects seen with other anti-depressants such as weight gain, sexual dysfunction and sedation.
Assessing effectiveness
Effectiveness of antidepressant treatments should be assessed by monitoring a number of key symptom areas, such as mood, sleep, interest and concentration. In addition, it is also important to assess levels of compliance and monitor for the presence of side-effects.
h2. Continuation of therapy
Patients treated with antidepressants should continue the drug for a minimum of 6 months (1 year for the elderly) from remission, at the full therapeutic dose.
Treatment-refractory MDD
It is important that a full and thorough assessment is made of such patients with confirmation of diagnosis. Care should be taken to exclude bipolar disorder.
Consideration of increased doses may be appropriate in individuals who are tolerating a drug and have shown an incremental response with increasing doses. However, prescribing beyond licensed doses should only be done by practitioners with expertise in the use of these
medications, and only after a full discussion with the patient, and informed consent has been obtained and documented in the patient’s notes.
The longest established pharmacological augmentation strategy is the addition of lithium to an antidepressant. In addition to augmentation agents, combinations of antidepressants are sometimes used. As with all management strategies that are supported by little or no evidence, they must be done with the informed consent of the patient, documentation in the patient’s notes and careful monitoring of side-effects and response.
Conclusions
MDD is a common, serious and recurrent condition. It has an enormous impact on individuals and society through increased mortality from a range of causes including suicide and the economic impact of impaired functioning of individuals. Whilst many controversies exist around the validity of the diagnostic concept, there is clear evidence of underlying biological, as well as psychological, abnormalities in suffers. Diagnosis is based upon arbitrary criteria that may be questioned with regard to validity but certainly improve reliability. Many treatment options are available including psychological and pharmacological therapies. It is important to treat the disorder effectively and as quickly as possible to minimise suffering and economic impacts of the illness.