Bipolar disorders (BDs) are chronic and progressive mood disorders characterised by manic, hypomanic or mixed episodes that typically occur in conjunction with depressive episodes.1 Globally, BDs are a leading cause of disability, with consequences that include long-term unemployment, comorbid medical illness, and suicide.2–5 Because of its recurrent pattern, people with BD are symptomatic for about half their lives, with the bulk of the psychosocial disability resulting from the depressive pole of the disorder.1,6 Despite this, much of the research for BD focuses on the manic phase of the illness, while most depression-related research focuses on unipolar depression. However, BD — and therefore bipolar depression — is a distinct illness that requires a specific treatment approach, tailored to individual needs. Here, we outline the distinct features of bipolar depression and present evidence-based treatment options.

BD is classically divided into bipolar I and II subtypes, but the bulk of the clinical data pertain to the bipolar I variant. It is a common disorder, with estimated lifetime prevalences of 0.6%–1.0% for the bipolar I subtype, 0.4%–1.1% for the bipolar II subtype, and 2.4%–5.1% for subthreshold (spectrum) forms of the disorder.1

The disorder characteristically begins in late adolescence, with the onset of subthreshold symptoms that are usually depressive in nature, followed by the later emergence of threshold depressive, manic or hypomanic episodes.7 People with BD commonly spend three times as long in the depressive pole of the disorder as they do in the manic pole.1 Bipolar depression, like its unipolar cousin, is undoubtedly heterogeneous, with biological, social, personality, trauma, lifestyle and substance misuse determinants. In contrast, mania appears to be more biologically grounded. This is of substantial relevance to treatment and should be considered when developing an individualised treatment package. Bipolar depression is particularly disabling, resulting in occupational and social impairment, and eroding quality of life. Depression and depressive mixed states are the illness phases that confer the greatest risk of suicide. The delay in the emergence of manic or hypomanic symptoms — the hallmark of the diagnosis — together with a high prevalence of comorbid disorders, typically leads to protracted delays in the correct diagnosis of BD and the initiation of appropriate management. Diagnostic delay can also result in patients receiving treatment that potentially worsens the core cyclicity of the disorder and its progression.8

The efficient management of bipolar depression is further hindered by a paucity of effective treatments, a problem that is compounded by a relative lack of clinical trial data. As there are few robust placebo-controlled studies of the treatment of bipolar depression, there is substantial dissent regarding optimal pharmacotherapy, particularly around the role of antidepressants.9 Recent well designed, large-scale trials of conventional antidepressants (selective serotonin reuptake inhibitors [SSRIs]) in BD have essentially been negative.10 There is also concern about the potential risk of inducing mania and worsening cycle frequency with antidepressant use in BD. Despite a limited evidence base for their effectiveness in this population, psychological treatments are often used in bipolar depression, based on extrapolation of data supporting the role of cognitive behaviour therapy (CBT) and related psychological therapies in unipolar depression and in maintenance treatment of BD.11

As a consequence, there is consensus that bipolar depression is the predominant unmet clinical need in patients with BD.12,13 The management of bipolar depression has by necessity become broader, to take the diversity of putative aetiological factors into account. A multifaceted approach to treatment is gaining traction and, clinically, has face validity. This broadening of therapeutic approaches recognises the polymorphous nature of bipolar depression, but also reflects the intrinsic ceiling effect that is commonly observed with pharmacological or psychosocial monotherapy. In clinical practice, pharmacotherapy is only modestly efficacious, largely because the underlying pathophysiology of the disorder remains unknown and because the mechanisms of action of most medications are poorly understood. Further, nearly all medications that are currently used to treat bipolar depression have been adopted from other primary indications.

There are three concurrent goals in the optimal management of bipolar depression: (i) to treat the acute episode effectively; (ii) to consolidate the gains of acute treatment and prevent depressive relapse or switch to hypomania or mania; and (iii) to manage potentially reversible risk factors.12 As BD is a chronic lifelong illness, it is essential to balance safety and tolerability of treatment against efficacy, and to build a long-term management plan based on informed, shared goals.

It is important to recognise that all interventions have the potential to cause harm. It is essential to weigh the risks and benefits of each treatment, taking into account a person’s demographic and clinical profile, values and preferences. While the risks of pharmacotherapy have long received recognition, the risks of inappropriately applied psychosocial interventions are also now beginning to be appreciated.14

To limit disability and maximise the likelihood of recovering psychosocial functioning,13 a suitable first-line treatment must be chosen.15 The choice needs to be tailored to the individual’s psychiatric history; in particular, comorbidities, pattern and severity of symptoms, prior illness course, history of response to and tolerability of treatments, family history of treatment response, and individual preference.13,15 Intriguing new data suggest that this latter factor potently predicts both treatment response and the development of adverse events.16 As treatments that are useful in acute treatment tend to be continued as maintenance therapy, treatments with maintenance efficacy should be prioritised over those without such an evidence base.13 This also means that long-term risk factors, including metabolic disturbance, may weigh against the long-term use of agents with short-term efficacy.

Where there is a partial or inadequate response to treatment, drug dosage needs to be optimised. In addition, adherence-related issues, medical or substance misuse comorbidities, and psychosocial factors must be considered and appropriately managed. Examination of psychosocial factors includes the role of personality, prior trauma, persistent psychosocial stressors and the development of abnormal illness behaviour.13,15,17

In the face of continued non-response to treatment or the development of unmanageable adverse events, augmentation or switching strategies should be considered. Augmentation is more likely to be used in situations of partial response and tolerability, whereas switching is more appropriate for non-response and intolerance.13,15 Assessment of the pattern of prior mood episodes to identify the predominant pole of illness (depression or mania) can often assist treatment choice, as predominant polarity tends to be relatively stable throughout the longitudinal course of the illness. Consequently, those agents with a documented profile of efficacy in the depressive phase (eg, lamotrigine or lithium) should be selected for treating bipolar depression.18

The natural history of the disorder is also informative. Depressive episodes can take many months to resolve, and the true effect of an agent on the long-term illness trajectory can only be determined over a prolonged period of observation. Therefore, any treatment trial needs to be of sufficient duration to ensure that potentially valuable therapies are not abandoned before they can demonstrate utility. Intensive psychoeducation regarding potential benefits and side effects of treatments can also help reduce non-adherence and early cessation of a potentially useful therapy.

Bipolar depression is the most common and difficult-to-treat phase of BD. There is a high incidence of subsyndromal symptoms in the disorder, which result in residual functional impairment and erosion of quality of life. Barriers due to stigma, acceptance, availability of treatment and psychoeducation need to be overcome to limit non-adherence to treatment and risk of relapse.48

The therapeutic benefits of any treatment choice need to be balanced against risk,49 and a long-term outlook is essential. In the context of a collaborative alliance between the patient and clinicians, continuous monitoring is also crucial. Pharmacotherapy should be integrated into a personalised psychosocial and lifestyle package of interventions that considers the person’s clinical profile and preferences.50 The treatment recommendations offered here are based on an evolving and incomplete evidence base, and should be used in conjunction with clinical judgement. Given that it is the predominant illness phase of BD, and the extant literature is patchy, high-quality trials of bipolar depression should be a priority.

Depression and dementia are common syndromes in older people and are usually managed by general practitioners. Comorbidity compounds the impact on patients, carers and health services.1–3 Yet, the relationship between the two is complex — features overlap and each seems to be a possible risk factor, symptom or consequence of the other. Thus, identification and effective management of depression in people with dementia remains a challenging task in clinical practice.

This article provides a clinically oriented selective review of current knowledge about depression in dementia, specifically aimed at primary care practitioners. Practice pearls are provided (Box 1). Although the literature overwhelmingly focuses on Alzheimer disease, here we also discuss mild cognitive impairment and other types of dementia. Mild cognitive impairment refers to a clinical status where a patient performs below norms on cognitive tests but does not have dementia. Either the patient or someone who knows him or her well should have noticed a change from premorbid cognitive function. Statistically, people with mild cognitive impairment are at increased risk of developing dementia over time, although the individual risk can vary significantly.4

Reported rates of depression in dementia vary substantially, depending on the population sampled, means of assessment and definition of caseness. Overall, most well conducted population-based studies report prevalences between 8% and 30%.1,5,6 In hospitalised patients and nursing home residents, the prevalence may be over 40%.1,5 Variance in prevalence estimates is greater in studies of mild cognitive impairment.6 A recent review of depression in mild cognitive impairment found median proportions of 44% in samples of hospital-based patients and 16% in community-based samples.1 The limited studies investigating depression in people with vascular dementia, Lewy body dementia or dementia associated with Parkinson disease suggest that depression may be more common in these syndromes than in Alzheimer disease.1

Reported risk factors include female sex, earlier age at dementia onset,7 a past history of depression or emotional problems,7,8 and recent losses.8 There is some evidence that, contrary to conventional wisdom, stage of dementia and insight into the diagnosis have little impact on depression rates.1,9

The consequences of depression in people with dementia include increased burden on patients and caregivers,10 increased caregiver depression,10 exacerbation of cognitive and functional decline,3,11,12 more dementia-related behavioural disturbance,13 poor outcomes from other medical or surgical interventions,3,14 earlier admission to nursing homes, and increased mortality.12,15–17

There is substantial academic interest in the relationship between depression and dementia, particularly regarding the direction of causality and possible disease mechanisms. There is now reasonable evidence that a history of depression is a risk factor for developing dementia, particularly when the depression occurs early in life or is severe.18 Conversely, incident depression occurring temporally close to the onset of cognitive impairment may represent very early or prodromal symptoms of dementia itself.1,19–21

A neuropathological mechanism common to both conditions, such as cerebrovascular disease or hippocampal atrophy, has been suggested.22–26 However, as with most psychiatric illness, the literature does not consistently support any “neat” pathophysiological hypothesis. It is likely that a complex intertwining of multiple factors is variably involved in different individuals.

Depression in people with dementia remains underdiagnosed, particularly in residential care settings.27,28 Disease, patient, clinician, family and system-level factors may all hinder accurate assessment.

Depression may present differently in people with comorbid dementia, particularly when the dementia is advanced. Although typical major depressive disorder (MDD) is seen, the clinical picture often lacks prominent sadness, hopelessness and guilt and is, overall, less severe.29 Anxiety, psychomotor retardation, loss of energy or appetite, anhedonia, irritability, delusions and hallucinations may all be more common (and prominent) than in people without dementia. These symptoms can also be part of the dementia itself or suggest delirium.3,24,30 Unexpected or rapid change in mood, cognitive deterioration, or increased behavioural and psychological symptoms of dementia (eg, disinhibition, agitation, anxiety or aggression) may be the only indicators of superimposed depression.13

Conventional techniques and instruments for assessing depression may not be reliable or practicable in people with dementia. When obtaining a patient history, patients may underreport, and their carers overreport, symptoms of depression.10 As dementia advances, cognitive and communication difficulties may also hamper assessment of the intrapsychic symptoms of depression, including subjective mood states, thoughts about oneself or others, and general outlook for the future. The use of standardised questionnaires is helpful only if they are validated in this population, which is not the case for many of the common depression rating scales.31

A useful scale is the Cornell Scale for Depression in Dementia (CSDD; Box 2).32 There are also modified Diagnostic and statistical manual of mental disorders, 4th edition (DSM-IV) criteria for MDD that include the diagnosis of Alzheimer disease.33 In Australia, the CSDD is incorporated into the Aged Care Funding Instrument, which is used to determine the funding allocated to aged care facilities for individual residents. However, due to limited time and staff in such facilities, attention to completing the CSDD is often cursory, and the results rarely alter management for individual residents. Moreover, serial evaluations are uncommon.28 Regularly combining use of rating scales with a thorough history would improve detection rates.

Obtaining as much history as possible regarding mood and behavioural symptoms from the patient and carers, such as family or residential care staff, is essential, particularly when communication difficulties are evident. This should be repeated at regular intervals (eg, 6-monthly) or if there is any evidence of a significant change in behaviour.28,34,35 It is important to enquire about a past history of depression and past treatments for depression, as well as family history, medical history, and drug and alcohol history. Physical illnesses, prescription medications, functional disability, social isolation, life stressors, bereavement and other losses are also important, as they may increase vulnerability to depression.1,29

Where there is clinical suspicion of depression (eg, change in mood or any difficult-to-explain change in behaviour), definitive treatment is usually worthwhile, especially when communication difficulties due to dementia act as a barrier to obtaining a detailed history.

Management of a patient with depression and dementia should encompass biological, psychological, social, cultural and spiritual factors, particularly those that may have precipitated or may be perpetuating the depression.

A focused physical examination and investigations are essential to exclude any treatable medical cause for low mood. Such causes are more likely to be present in older people and may include physical illness and prescription medications. Common medical causes of depressed mood are listed in Box 3, and important screening investigations for an organic cause are listed in Box 4. Patients also frequently present with physical illness and depressed mood where there is a known association, but it is neither causal nor reversible (eg, depression and ischaemic heart disease). Overall physical health should be reviewed and optimised, and the depression should be specifically treated. Addressing vascular risk factors is particularly important.

Risks associated with depression in people with dementia must be considered throughout, as they may determine the type, location and urgency of treatment. Every patient with depression should be asked directly but sensitively about suicidal thoughts, plans and intent (Box 5). Suicide risk also depends on available protective supports, supervision and the patient’s access to means. Other risks include harm to others or to relationships due to agitation, aggression or irritability; loss of accommodation or a move to institutional care; and medical compromise. Generally, most depression in people with dementia can be managed in the community.

Depression is common in people with dementia, and the relationship between mood and cognitive symptoms is complex. The nature of this relationship, disease stage, and environmental and clinician factors all contribute to underdiagnosis and undertreatment. Although evidence regarding antidepressant treatment is limited and equivocal, there is no cause for therapeutic nihilism. Organic causes of depressed mood should be excluded, physical health optimised, and medications, where possible, rationalised. Best management includes individually tailored psychosocial strategies and, in moderate to severe depression, judicious use of antidepressant medication with a “start low, go slow” approach. Regular review and effective engagement of carers are both essential and may have significant positive impacts for patients and carers. Difficult-to-treat or complex depression is an indication for specialist referral.

It is well recognised that depression frequently does not respond to standard pharmaceutical treatment and psychotherapy techniques.1,2 Non-pharmacological biological treatments have a long history of use in difficult-to-treat psychiatric illnesses such as depression. With increasing recognition of the frequency and impact of difficult-to-treat depression and a variety of technological developments, the past 10 years have seen a dramatic increase in interest in development of novel brain stimulation techniques. Here, I provide an overview of the characteristics and current status of development of non-pharmacological biological treatments for depression (Box).

Electroconvulsive therapy (ECT) is the most widely used and effective non-pharmacological biological treatment for depression and remains the most effective treatment for difficult-to-treat depression. Its use is particularly indicated when a rapid antidepressant response is required, such as in highly suicidal patients.

Although ECT has been in use for well over 50 years and is a commonly applied clinical tool, questions regarding optimal methods of administration remain. Cognitive side effects, especially anterograde and retrograde amnesia, remain problematic, as does the substantial stigma associated with this treatment in the community. Over the past 10 years, slow progress has been made in refining ECT administration techniques, especially focused on trying to achieve maximum therapeutic benefit with minimal cognitive side effects. Studies have tended to confirm that right unilateral ECT at sufficient intensity has similar efficacy to bilateral treatment,5 although bilateral treatment may result in a more rapid clinical response. Bifrontal stimulation has not proven to be a substantial advance over other more traditional approaches.5 Considerable focus has also been given to the use of ultra-brief pulse-width stimulation to try to minimise cognitive side effects. Similar efficacy has been reported in some studies,6,7 although response to ultra-brief treatment may take longer than standard approaches8 or be somewhat less than the response to bilateral treatment.9 ECT can be life-saving, especially in urgent clinical situations, and remains a valuable tool for patients with severe depression that does not respond to other therapies.

Repetitive transcranial magnetic stimulation (rTMS) is a novel, non-convulsive brain stimulation technique that involves the repeated application of a time-variable magnetic field to superficial areas of the cortex through a stimulating coil held above the scalp.10 Magnetic fields applied at sufficient intensity to the brain will induce electrical activity in cortical neurones, including depolarisation. Repeated stimulation of local groups of neurones will result in changes in local cortical activity and the stimulation of distal brain regions through the activation of projecting neurones. High-frequency rTMS (pulses applied at 5–20 Hz) is known to increase local cortical excitability, and low-frequency stimulation (usually 1 Hz) has the opposite effect.11 In a therapeutic context, rTMS is usually provided in sessions lasting between 20 and 45 minutes, 5 days a week, for 3–6 weeks.

In the initial studies, high-frequency rTMS was applied to the left dorsolateral prefrontal cortex (DLPFC), following observation of this brain region as underactive in patients with depression.12 Many sham-controlled studies, including two large multisite trials, have investigated the efficacy of this form of stimulation. Several meta-analyses have summarised the results of these trials, with the more recent analyses showing clear positive antidepressant effects. For example, in a meta-analysis involving 30 trials and 1164 patients, there was a highly significant effect of active treatment compared with placebo on the average reduction in depression severity scores (P < 0.001).13 The included trials involved a mixture of patients with treatment-resistant and non-treatment-resistant depression and produced effect sizes (typically moderate) similar to those seen with antidepressant medication.13 Trials have also compared rTMS with ECT, but substantial inequalities in the treatments provided in these studies (eg, the number of treatment sessions) make interpretation of the results problematic. Both of the two large multisite trials (one independently sponsored and one industry sponsored) showed greater antidepressant effects of active rTMS compared with sham treatment.14,15 Remission rates (usually defined as a reduction of rating scale scores below a certain low cut-off) were similar to those seen in medication trials with comparable patient populations.

The result of these trials has been the development of clinical rTMS programs in several countries, including the United States, Canada, Germany and Australia. One rTMS device was licensed for depression treatment in the US in 2008 and is now used in over 200 clinical services. The first publicly funded rTMS treatment program in Australia commenced operation in Victoria in early 2012. Despite this clinical progression, substantial questions remain regarding the optimal methods for rTMS application. High-frequency stimulation to the left DLPFC is not the only effective method for rTMS application. There is evidence for the equivalent efficacy of low-frequency stimulation applied to the right DLPFC and interest in the development of bilateral methods of stimulation.16 Stimulation efficacy may be found to improve with the use of better brain site targeting and possibly with novel, more complex stimulation methods. Research is also required to define the best methods of maintenance rTMS.

Generally speaking, rTMS treatment is safe and well tolerated.17,18 There is a very low risk of incidental seizure induction, and some patients find the procedure uncomfortable, or it may produce a transient headache. Switch to mania in patients with bipolar disorder is also possible. However, overall rates of treatment adherence are very high and no other major adverse consequences have emerged, despite more than 15 years of clinical trials. rTMS is likely to be a suitable approach for patients in whom one or more medication treatment trials have failed but who do not require a rapid antidepressant response that would justify immediate ECT.

Magnetic seizure therapy (MST) is a technique that combines both rTMS and ECT. During MST, a high-powered rTMS device is used to induce a seizure as an alternative to the electrical current used in ECT. The procedure is otherwise performed in a similar manner to ECT, involving a general anaesthetic and muscle relaxant.

The potential for MST arose from the observation that it might be possible to dissociate the therapeutic benefits of ECT from its cognitive side effects — specifically, that the benefits might arise through the induced seizure but the side effects from the electrical method of seizure induction. Studies investigating the safety of MST have been conducted for more than 10 years, supporting the notion that magnetic seizure induction does not appear to produce substantial cognitive side effects. Therapeutic studies have been limited until recent years by the power of stimulation devices. Trials using rTMS stimulation at up to 100 Hz are now being conducted, with early data suggesting similar therapeutic efficacy to ECT, with a benign cognitive profile.19 For example, in the first small randomised comparison, response rates (defined as a 50% reduction in Montgomery–Åsberg Depression Rating Scale scores) were 60% for MST and 40% for ECT.19

Substantive clinical trials of MST are required to establish its efficacy. However, it could be relatively rapidly taken up in clinical practice, using established ECT infrastructure, if its benign cognitive profile is matched by substantial therapeutic efficacy.

Brain activity can also be changed with the application of a very low-voltage electrical current, termed transcranial direct current stimulation (tDCS). This technique was first proposed in the 1950s, but there has been a resurgence of interest in the past 10 years as studies have demonstrated clearly that it has definite biological effects. When a low-amplitude (1–2 mA) direct current is applied to the brain through two surface electrodes placed on the scalp,20 cortical activity under the anode (positive electrode) is increased due to a shift in membrane polarisation that results in secondary synaptic effects. In contrast, activity under the cathode is reduced.

Observation of these effects led to interest in the use of anodal stimulation applied to the left DLPFC for treating depression. The efficacy of this approach has been assessed in a series of small randomised controlled trials, and the results have recently been summarised in a meta-analysis that included six trials (involving a total of 96 active and 80 sham treatment courses).21 A positive antidepressant effect was noted across this limited sample. In a recent single-site study with a larger patient sample (n = 64), tDCS produced a greater reduction in mean depression rating scale scores than did sham stimulation, although there was no difference in response rates and no patients achieved remission status.22 Although no large studies have yet been published, the safety profile of tDCS appears promising. The procedure can result in local irritation or headache, but these effects appear to be predominantly transient.23,24

tDCS shows promise as an antidepressant treatment but remains in very early stages of development. Its potential applicability is wide, as tDCS machines can be produced at very low cost, offering the possibility of it being made available in less affluent countries.

Vagus nerve stimulation (VNS) is a procedure involving the surgical implantation of a pulse generator (similar to a pacemaker) in the chest, connected to a stimulating electrode attached to the vagus nerve in the neck.25,26 Stimulation of the vagus nerve results in activation of a variety of subcortical brain structures, which may reduce seizure frequency in refractory epilepsy and also has antidepressant effects.

Following approval of VNS for treating epilepsy, trials investigating its antidepressant activity were conducted. Initial open-label efficacy data were promising, although a multisite randomised trial produced disappointing results, with a very low response rate no different from that for sham stimulation.27 However, long-term follow-up suggested that a small group of patients do respond to VNS, even if they have a long history of illness and treatment resistance.27 Response appears to take some time to develop but persists with continued use.27 The main side effects with VNS include an alteration of voice, neck discomfort, cough and dysphagia.28

VNS treatment for depression has been approved in the US since 2005 for patients in whom at least four medication trials have failed, but similar approval has not been granted in Australia and VNS is not commonly used in this country for this indication.

Deep brain stimulation (DBS) is the most invasive of the modern brain stimulation approaches to the treatment of depression and other difficult-to-treat psychiatric disorders, such as obsessive–compulsive disorder. Like VNS, DBS was developed for a neurological indication — Parkinson disease — where it is relatively widely used. It involves the implantation of a pulse generator connected to two stimulating electrode wires, which are surgically placed in specific brain regions. Four electrodes are located at the ends of the wires. After implantation, a clinician adjusts a variety of stimulation parameters, including voltage, pulse width and frequency, to try to achieve symptom abatement.

DBS trials in depression have focused on two brain regions. The majority of patients have received implantation in the white matter next to the subgenual anterior cingulate cortex, an area of the brain repeatedly identified in brain imaging studies as related to antidepressant response. Response rates to stimulation in patients with highly difficult-to-treat depression have been reported as around or greater than 50%, with persistent benefit over a 3-year follow-up period.29 Response rates close to 50% have also been seen in small groups of patients who received implantation in the anterior limb of the internal capsule or in the nucleus accumbens at its ventral end. For example, in 15 patients, stimulation of the internal capsule resulted in a 40% response rate at 6 months and a 53% response rate at final follow-up (at a mean of 23.5 ± 14.9 months).30

Side effects can arise with the DBS surgical procedure, as well as with the stimulation. The former can include haemorrhage, seizure induction, infection (usually superficial) and other anaesthetic complications, which are fortunately uncommon. Side effects related to stimulation can include the induction of lowered mood, fear and anxiety.31 These are reversible — a substantial advantage over the lesional psychosurgical procedures that DBS has mostly replaced.

Considerable attention has been attracted to the use of DBS in recent years but, because of its invasive nature, it is likely to remain reserved for patients with the most severe and difficult-to-treat depression. Although mostly being provided in clinical trials, it has already replaced the use of lesional psychosurgery in most countries where it is being evaluated. Further research is required to define its role and the most effective method of administration.

Several techniques that are yet to move into the clinical domain are in the early stages of exploration as potential ways of modulating brain activity. For example, recent research has demonstrated that low-intensity ultrasound has the capacity to produce neuronal depolarisation, possibly through the mechanical stimulation of ion channels.32 This potential application of ultrasound differs from the use of high-intensity ultrasound as a means of ablating tissue and involves intensities not associated with tissue damage. Research is also investigating the application of low-field magnetic stimulation, following the observation of mood changes with specific magnetic resonance imaging paradigms33 and the effects of other forms of cranial electrical stimulation. Stimulation of the cortical surface with epidurally implanted electrodes has also demonstrated some antidepressant potential in very early pilot-stage research.34

Non-pharmacological biological approaches, mostly in the form of ECT, have contributed to the management of depression for many years, and there is currently a rapid expansion of potential therapeutic tools in this area. rTMS is increasingly being used in clinical practice, and other treatments such as VNS have been approved for use in some jurisdictions. Other approaches, some with considerable apparent potential to contribute to the clinical management of depression, are in earlier stages of evaluation. As some of these treatments, such as rTMS, require new clinical infrastructure, the development of services is likely to be inconsistent and variable for some time. Ongoing work is required to define which treatments are likely to be most useful, and in which patient groups.