Progress in Personalising and Optimising the Management of Depression and Internalising Disorders

For patients and clinicians there have been no “magic bullet” advances in the management of depression this century. The three core recommended treatment modalities – psychological therapy, antidepressant medication, and exercise - remain the same, although uncertainty persists as to when to apply them in the correct combinations for depression at different levels of severity [1]. Depression as a disorder has a higher level of contextual/placebo effects influencing trial outcomes than any other medical or psychiatric disorder [2,3], which results in small effect sizes and a low level of evidence regarding the relative efficacy of individual antidepressant interventions when compared against each other [4]. The consequent low quality of evidence is reflected in the diversity of recommendations in depression clinical practice guidelines (CPGs). There are more than 60 depression CPGs used internationally [5], and a scoping review [6] of the 23 most commonly used CPGs published in 2019 found that the number of recommendations for treating depression varied between one and 199. Most recommendations focus on the use of more than 20 antidepressant medications [7] in combination with psychotherapeutic interventions developed more than 25 years ago [4]. Psychiatrists, general practitioners, and psychologists regard depression as a complex and heterogeneous condition that requires an eclectic/pluralistic management approach [8,9]. However, as different professional groups may have adopted different models of care [10-12] there may be variations in the treatment that patients actually receive [13]. In the continuing absence of a magic bullet therapy the challenge is to develop a framework whereby all patients receive the same optimal care, but that care can be personalised within this framework [9] to match the context of the individual. 

Because of the “effect size” problem of the traditional RCT in depression this article interrogates the extensive literature from a different perspective in seeking recent advances in depression. It identifies four areas of progress which clinicians can potentially translate into improved outcomes.

This article uses narrative review, based on previous hand literature searches conducted by the author [14,15] and his co-authors [3,16] and published in peer reviewed journals. The narrative review has a particular focus on network meta-analyses (NMAs), as the best means of assessing depression outcomes.

Four treatment advances in treating depression were identified. 

• Recent Advances in Medical Statistics Applied to Depression Outcome Research 

Over the last decade, NMA has been recognised as the best statistical technique to analyse depression outcome research [17,18]. In disorders such as depression where there are several potential treatment modalities, applying Bayesian statistics enables direct and indirect comparison of data [19]. This is particularly pertinent in conditions where contextual effects are prominent, as the indirect comparisons act to offset and minimise bias [18]. NMA therefore theoretically gives a higher level of evidence than pairwise meta-analysis or systematic review which are the main tools traditionally used for drawing up depression CPGs. 

Some published NMAs have compared >60 putative treatments for depression [20,21], but introducing this degree of heterogeneity is less effective in minimising bias. 

Recent depression NMAs that compare the three mainstays of depression treatment – psychological therapy, exercise, and antidepressant medication – conclude that these modalities have similar efficacy in MDD, and produce better outcomes if used in combination [17,22,23]. These conclusions represent a treatment advance in depression management, though unless other treatment advances are integrated it remains unclear which combinations should be used in which order for different levels of depression severity [1]. 

• Recent Advances in Using Exercise as a First Line Treatment for Depression 

Exercise as an effective treatment for depression has been in the public domain for more than 25 years [24,25] so is not a recent advance. Cochrane reviews [26] provides a moderate level of evidence that aerobic exercise, social prescribing, and passive exercise including yoga are all effective in depression, though there is little evidence that exercise is used routinely by general practitioners, psychiatrists or psychologists in managing depression. Doubts have been expressed about the practicalities of implementing exercise in the most severely depressed [27], and confidence in this data is limited due to the usual problem of bias in the RCTs [26]. However, a recent NMA [23] provides stronger evidence for efficacy, particularly if exercise is combined with other antidepressant treatment modalities. Furthermore, this study also provides data on the level of exercise required: aerobic exercise is best, but walking, yoga and passive exercise are almost as good [23]. 

Clinicians may be more inclined to use exercise in depression if they knew how it worked, i.e. how it exerted its mode of action. There is some neuroradiological evidence to support the theory that exercise works by correcting and realigning dysfunctional fronto-limbic circuits demonstrable in depression [3]. Exercise stimulates release of interleukins and brain derived neurotropic factor (BDNF), thus stimulating ionotropic and metabotropic neuroplasticity [28]. This proposed mode of action is similar to that of CBT [29] and antidepressant medications [30,31], and suggests that these modalities used in combination may exert synergistic benefits [32]. The overlap between exercise and behavioural activation - a cognitive behavioural technique – on neuroplasticity and brain architecture is noteworthy [14]. 

In summary, a recent advance is that exercise should always be used as a first line treatment for depression, irrespective of the age of the patient and the severity of the depression. 

• Recent Advances in Understanding the Genetic Epidemiology of Depression Alongside other Mental Disorders 

Confusion regarding the classification of depression has held back depression outcome research for decades. There is consensus that the mental disorder of depression can be the final common pathway of multiple psychosocial stressors, interacting with genetic susceptibility [33,34]. However, it is not known if depression is one disorder with a wide spectrum of severity [35] or two separate disorders called major/more severe depression versus minor/less severe depression [36]. There is no international agreement, as represented by the ICD and DSM classifications, on how to initially distinguish bipolar from unipolar depression, nor how to grade the severity of depression. Descriptive terms defined by expert consensus such as “mild, moderate and severe” have limited scientific validity or clinical utility. Therefore, a population based study published in Nature in December 2025 [37] can be regarded as a treatment advance in managing depression, as it sheds new light on genetic susceptibility for mental disorder. 

The authors of the Nature study, based in Norway, examined DNA data from more than 1 million individuals diagnosed with psychiatric disorders and 5 million individuals without a psychiatric diagnosis. Using genetic association and multiple statistical techniques they mapped genetic profiling against mental disorder, and found that approximately 50% of subjects had genetic vulnerability for at least one of 14 mental disorders. 

The 14 mental disorders clustered into five categories based on a high level of shared genetic data. 

Psychotic disorders – schizophrenia and bipolar disorders

Internalising disorders – MDD, anxiety disorders, PTSD

Substance use disorders – opioid, cannabis, alcohol, and nicotine dependence disorder

Neurodevelopment disorders – autism and ADHD spectrum disorders

Compulsive disorders – OCD, anorexia nervosa, Tourette disorder 

The main area of interest for progressing depression management is the subcategory of internalising disorders, which comprises depression, anxiety, and post-traumatic stress disorder (PTSD) [38]. Individuals with internalising disorder inherit a polygenic susceptibility to becoming depressed, but at different times of life this may manifest as anxiety, or (following psychological trauma) as PTSD. Such “internalising” individuals are likely to be people who have lifelong anxiety and a tendency to anhedonia and dysthymia, though may only tip over into caseness at times of stress, if protective factors are overwhelmed. 

Advances in genetic epidemiology, in combination with data from the National Comorbidity Surveys [39,40], therefore suggest that depression is indeed a unitary disorder but with three potential pathways to become depressed, as follows:- 

A). Affective Disorder: Firstly, if the individual inherits psychosis genes this may manifest as bipolar depression or seasonal affective disorder which will usually require intensive pharmacological interventions short and long term, potentially including antipsychotics and mood stabilisers. Such individuals may be at higher risk of developing difficult to treat depression [41], with high risk of relapse [42] requiring monitoring and a “long term condition” approach for optimal outcome [11]. 

B). Internalising Disorder: Secondly, the individual may become depressed as a consequence of inheriting a susceptibility to internalising disorder, which usually requires combinations of exercise, CBT, and antidepressants for optimal outcome, supplemented by CBT for anxiety and trauma based therapy [43] for PTSD at points during the lifespan. 

C). Non-genetic Depressive Disorder: Thirdly, the individual may become depressed in the absence of any genetic susceptibility, as a consequence of organic factors or unremitting severe stress. National Comorbidity Surveys [39,40] suggest that this type of depression is common in countries with steep wealth and health inequalities and relative poverty [44]. In these circumstances antidepressant medication should be avoided initially as depression may remit if the stressors attenuate. Core treatments should initially focus on exercise, phased trauma based therapy and CBT [14], and active treatment of medical and psychiatric comorbidities [12]. Watch and wait [11] is restricted to antidepressant medication in this third subgroup, whilst the response to exercise plus psychological therapy is monitored. 

In summary, advances in genetic epidemiology suggest that depression is one unitary disorder and the final common pathway of multiple interacting genetic and environmental influences., which can nonetheless be subdivided. The three subdivisions of affective disorder, internalising disorder, and non-genetic depression are unrelated to depression severity or risk. Optimal treatment of depression involves combinations of exercise, psychological therapy, and antidepressant medication, and now genetic profiling has the potential to personalise each component to the context of the individual. 

• Recent Advances in Treating Comorbidities of Depression 

Most cases of depression are comorbid with other physical and mental disorders, which may act as predisposing, precipitating and perpetuating factors in the depressive disorder. For example, the commonest risk factor for depression in older people is medical illness [45], and it is increasingly recognised that a common risk factor for depression in younger people is substance misuse and/or neurodiversity disorder (ADHD) [46]. Clinical experience in treating depression suggests that it is necessary to treat the whole person, i.e. it is necessary to treat depression and its comorbidities simultaneously, in order to achieve a lasting good outcome [1,9]. Another problem with outcome research in depression is that patients with comorbidities are frequently excluded from RCTs, so the imperative to treat the whole person is not adequately reflected in depression CPGs. Advances in treating comorbidities of depression suggest that optimum treatment of depression requires attention to comorbidities too [9].

Depression is the most common mental disorder with the highest global burden of disease [47], and is arguably the physical and mental disorder that has benefitted least from an evidence based medicine approach. This is partly because the “effect size problem” - unique to depression - confounds research outcomes [3]. Data derived from pairwise meta-analysis has a high risk of bias in results [17] and data drawn from systematic reviews has a high risk of bias in conclusions [4], reflected in CPGs of variable quality and applicability [5]. This justifies the unorthodox methodology used in this article to identify recent advances, and uniquely in depression suggests placing a higher emphasis on NMA to guide treatment priorities, as an orthodox approach has been unsuccessful in improving depression outcomes. The treatment advances identified by this methodology are based on four recently published articles [9,17,23,37] which suggest that at current levels of knowledge optimal treatment of depression is not necessarily complex or expensive. In assessing the context of depression [34], clinicians need to prioritise family history and identify the presence of psychological trauma or psychosis, accompanied by accurate diagnosis of comorbidities. In treating incident depression, clinicians need to demonstrate that they understand the context in which depression has arisen [3,14], whilst using combinations of exercise, psychological therapy and off patent psychotropic medication. In assessing the need for follow up genetic epidemiology can alert clinicians to prognostic risk in identifying patients with a likely poor prognosis, with psychotic depression being a particular red flag. For patients who develop depression in the absence of genetic susceptibility, treatment of psychological trauma and comorbidities assumes greater importance. Recent advances in NMA and genetic epidemiology thus provide a framework for simultaneously optimising and personalising treatment modalities for the individual, with the potential to improve outcomes. Existing depression CPGs need to be updated to incorporate the higher quality of evidence provided by rigorously conducted NMAs [48], so that exercise is given a higher priority in the routine management of depression at all levels of severity. 

This opinion article is limited in that it has presented no new data on patient outcomes. It is not a systematic review so may have missed some relevant literature. The methodology has instead drawn together recently published research from diverse areas of literature so that the theoretical advances identified can be used in clinical practice. Future research needs to focus on NMAs that can assess outcomes in depression comorbid with physical and mental comorbidities; how to engage depressed people more effectively so that they can benefit from combination therapies; and developing care pathways that match genetic subtypes of depression to long term outcome.

This article has identified four advances in the long-term treating depression that can be condensed into two main advances that clinicians can use to improve outcomes, with few resource implications. Firstly, exercise should always be used in optimal management of depression. Secondly, depression now can be subdivided into three categories – affective disorder, internalising disorder, and non-genetic depression - in order to personalise therapy to the individual.

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