The woodland has a number of blogs in relation to ‘therapy resistant despair’ taking a look at a spread of matters from the affected person expertise to the associated fee effectiveness of interventions corresponding to long run psychoanalytic psychotherapy.
I put therapy resistant despair (TRD) in italics above as chances are you’ll be stunned to know that there isn’t any consensus on its definition, which in flip signifies that the incidence charges fluctuate and there are not any constant medical pointers in relation to therapy (Gabriel et al 2023).
The US Meals and Drug Administration and the European Medicines Company have adopted essentially the most used definition of TRD (insufficient response to a minimal of two antidepressants regardless of adequacy of the therapy trial and adherence to therapy). It’s presently estimated that at the least 30% of individuals with despair meet this definition and so the burden of this side of despair just isn’t insignificant (McIntyre R et al 2023).
The Maudsley Prescribing Tips (Taylor et al 2021) first alternative choices for administration of TRD embrace augmentation with lithium and quetiapine. This weblog appears to be like on the new randomised managed trial by Prof Tony Cleare et al, printed immediately in The Lancet Psychiatry, instantly evaluating the medical and value effectiveness of the 2. This paper is especially fascinating because the trial (the LQD examine (Lithium versus Quetiapine in Melancholy)) has a for much longer observe up interval than earlier research, enabling a ‘actual life’ comparability.
The LQD examine, printed immediately within the Lancet Psychiatry compares the medical and value effectiveness of lithium and quetiapine for therapy resistant despair.
Strategies
So, this trial is a *takes a deep breath* “section 4, pragmatic, open label, parallel-group, randomised managed superiority trial, evaluating the medical effectiveness and value effectiveness of lithium versus quetiapine augmentation of antidepressant medicine in individuals with treatment-resistant despair.”. Let me break that down for you:
- Part 4: medicine is accredited and being utilized in follow. These trials take a look at long run security and effectiveness in follow
- Pragmatic: trying on the effectiveness of medicines in actual life conditions
- Open label: individuals and researchers know which therapy the individuals are receiving (non-blinded examine)
- Parallel group: two lively therapy teams, that are then in contrast
- Randomised managed superiority trial: individuals have been randomly assigned to therapy teams and reviewed as to which therapy performs higher.
Scientific effectiveness course of: Following random allocation to therapy, trial clinicians might determine whether or not to proceed with prescription of the allotted medicine primarily based on pre-prescribing security checks and medical judgement. All individuals, no matter trial medicine standing, have been adopted up over 12 months until they actively withdrew.
The first outcomes have been:
- The Fast Stock of Depressive Symptomatology (QIDS-SR) , used as a weekly measure of temper state and
- Time to discontinuation of therapy.
Weekly knowledge on QIDS-SR, Work and Social Adjustment Scale (WSAS) and trial medicine standing have been collected through a web-based platform, True Colors.
Price effectiveness course of: The Shopper Service Receipt Stock was used at baseline, 8, 26, and 52 weeks. This instrument collects knowledge on health-care service use, together with the quantity and period of contacts with main and secondary health-care companies. High quality-Adjusted Life Years (QALYs) have been used to measure well being advantages.
Outcomes
Over a 4.5 12 months interval (Dec 2016 to July 2021) 262 sufferers have been screened for eligibility from 6 NHS Trusts throughout England. The inclusion standards included:
- ≥ 18 years
- Underneath the care of a GP or psychological well being service
- Present depressive episode assembly DSM-5 standards for main depressive dysfunction (single or recurrent episode)
- Rating of ≥ 14 on the 17 merchandise Hamilton Melancholy Ranking Scale
- Insufficient response of the present episode to 2 or extra antidepressants, prescribed for at the least 6 weeks at therapeutic dose
- Present antidepressant therapy unchanged and at therapeutic dose for at the least 6 weeks; and
- Had been capable of present written knowledgeable consent
Exclusion standards included (however not restricted to)
- Prognosis of bipolar dysfunction or present psychosis
- Sufficient use of lithium or quetiapine of their present episode
- Present use of one other atypical antipsychotic.
There have been main, secondary and tertiary outcomes within the examine. For this weblog I’ll concentrate on the first outcomes and be aware any key outcomes from the secondary outcomes (tertiary outcomes weren’t included on this publication).
212 sufferers have been randomly assigned:
- 105 assigned to lithium; 21 didn’t obtain or provoke lithium however remained within the trial. 66 supplied knowledge at 52 week observe up
- 107 assigned to quetiapine; 12 didn’t obtain quetiapine however remained within the trial. 78 supplied knowledge at 52 week observe up
Scientific effectiveness outcomes
Main outcomes
- General burden of depressive symptom severity over 12 months
- Time to all trigger discontinuation
Contributors within the quetiapine group had a decrease general burden of depressive symptom severity than individuals within the lithium group over 12 months. The QIDS-SR knowledge factors have been mapped over the 12 months and the world below the curve calculation used as a measure of depressive symptom burden. The realm below the curve was smaller for Quetiapine: (space below the distinction curve –68.36 [95% CI –129.95 to –6.76]; p=0.0296).
Time to trial medicine discontinuation didn’t differ considerably between the 2 teams; the median time was:
- 365.0 days (Inter-Quartile Vary, IQR 57.0 to 365.0) within the quetiapine group
- 212.0 days (21.0 to 365.0) within the lithium group
- Adjusted hazard ratio [HR] 0.72 [95% CI 0.47 to 1.09]; p=0.1196.
Given the extensive IQR and huge discrepancy between the respective medians, we should take into account this “absence of proof” slightly than “proof of absence”.
When it comes to secondary outcomes, individuals within the quetiapine group had considerably decrease MADRS (p=0.0435) and WSAS scores (p=0.0071) at week 52 than individuals within the lithium group. No vital variations have been famous within the different secondary outcomes which included bodily well being parameters and antagonistic occasions (see paper for full particulars). An fascinating unfavorable end result was that no weight acquire was noticed throughout time within the quetiapine group.
Price effectiveness outcomes
In contrast with lithium, quetiapine was dominant. Prices have been decrease whereas advantages have been larger.
From an NHS and private social companies perspective, quetiapine was related to decrease price and bigger acquire in QALYs, than lithium. The incremental internet well being advantage of Quetiapine was 0.097 over lithium (with any constructive end result indicating choice to the in contrast various). Further price effectiveness evaluation can be found within the appendices of the paper which define that quetiapine is essentially the most cost-effective possibility based on the NICE willingness-to-pay threshold.
The quetiapine therapy group had a decrease general burden of depressive symptomatology than lithium.
Conclusions
The authors concluded that:
our findings recommend a average and clinically related advantage of quetiapine over lithium for long-term therapy of individuals with treatment-resistant despair.
And this examine:
…extends the earlier discovering that quetiapine is non-inferior to lithium over the brief time period and recommend superiority over the long run.
In comparison with lithium, quetiapine is essentially the most cost-effective possibility in relation to the NICE willingness-to-pay threshold.
Strengths and limitations
This paper has some actual strengths in that its major goal was to imitate real-life medical selections and sufferers. There was lived expertise involvement in designing and working the trial and affected person and public involvement members have been supportive of the weekly QIDS-SR assessments to supply a greater indication of the course and long-term period of final result for what could be a fluctuating medical course in therapy resistant despair (TRD). Following sufferers up for 1 12 months was a giant plus.
As a result of nature of the trial, clinicians weren’t blind to allocation, nonetheless the authors report that ‘clinician rated final result measures have been assessed by masked raters and statisticians have been unaware of group allocation till the information evaluation section’ to attempt to cut back bias as a lot as attainable.
With each trial there will probably be limitations and this paper is not any exception. Having clinician judgement as as to if the allotted medication is prescribed doubtlessly introduces allocation bias.
The affected person teams have been randomised based on diploma of therapy resistance (failure of two versus three or extra antidepressant therapies within the present episode) they usually used ‘block randomisation with randomly various block sizes’, nonetheless inside the outcomes there isn’t any reference as to what number of have been in every group or whether or not the outcomes correlated to this.
A lot of the knowledge relied on self-reports. Though this methodology was developed in partnership with affected person teams, the burden might have contributed to attrition.
In the course of the trial, the pattern measurement was lowered from 276 to 214 as a result of challenges with recruitment. Energy calculations have been accomplished and have been 80% for time to discontinuation and 96.5% energy with an impact measurement of 0.38. It’s nonetheless unclear if the discontinuation charges, impact sizes and attrition charges have been modified from the unique planning when calculating these. There seemed to be doubtlessly regarding gaps within the 52 week assortment knowledge, extra so for lithium (37% for the lithium group and 27% for the Quetiapine group) and the authors be aware substantial lacking knowledge for a number of the secondary outcomes.
General, there was a number of attrition, which ought to warning our interpretation of those outcomes. The intention to deal with evaluation solely included 66/104 and 78/107 of the lithium and quetiapine sufferers respectively. The totally different ranges of attrition in every group might imply that we’re now not evaluating like with like throughout the teams.
Lastly, the inhabitants examined was predominantly white (89%) which can restrict the flexibility for generalisation to all populations.
Mimicking actual life medical follow over a 12 months comes with it’s personal limitations.
Implications for follow
Sufferers who’ve despair which is ‘tough to deal with’ are ‘clinically difficult’ and endure a big burden from the illness. Each lithium and quetiapine are widespread choices for augmentation and this paper highlights that quetiapine may very well be extra efficacious and value efficient than lithium. The size of observe up of the examine makes this encouraging and positively value contemplating. The ability of the examine and the slightly heterogeneous group of severity might restrict leaping to a right away use of quetiapine over lithium, but when there was future replication of this examine and outcomes, then that would definitely be convincing.
The authors are clear although that Lithium stays an efficient therapy possibility. It’s possible that the medicines may have totally different advantages for various individuals (e.g. issues in relation to sleep, urge for food, nervousness) and so therapy needs to be tailor-made to those wants. Nonetheless, if lithium and quetiapine are equally acceptable then quetiapine could pip lithium to the publish.
Having clear medical pointers in relation to methods for ‘tough to deal with’ despair and/or when it turns into ‘therapy resistant’, appears a precedence in order that future analysis might be evaluating apples with apples.
On the time of penning this, there’s a complicating consider that there’s a nationwide scarcity of modified launch quetiapine and we’re having to maneuver sufferers onto instant launch Quetiapine which has a special aspect impact profile and should not produce outcomes replicable to the examine.
Quetiapine might pip lithium to the publish if on an excellent discipline.
The private influence of therapy resistant despair can’t be underestimated and I’m certain they might agree with the phrases of Bon Jovi ‘I simply need to stay whereas I’m alive…it’s my life’.
Assertion of pursuits
I’ve no battle of pursuits to reveal
Hyperlinks
Main paper
Anthony J Cleare, Jess Kerr-Gaffney, Kimberley Goldsmith, Zohra Zenasni, Nahel Yaziji, Huajie Jin, Alessandro Colasanti, John R Geddes, David Kessler, R Hamish McAllister-Williams, Allan H Younger, Alvaro Barrera, Lindsey Marwood, Rachael W Taylor, Helena Tee, and on behalf of he LQD Research Group. (2025) Scientific and cost-effectiveness of lithium versus quetiapine augmentation for treatment-resistant despair in England: a practical, open-label, parallel-group, randomised managed superiority trial. The Lancet Psychiatry 2025. DOI: 10.1016/S2215-0366(25)00028-8
Different references
Gabriel FC et al (2023) Tips’ suggestions for the treatment-resistant despair: A scientific evaluate of their high quality. PLoS ONE 18(2): e0281501.
McIntyre RS, et al (2023) Remedy-resistant despair: definition, prevalence, detection, administration, and investigational interventions. World Psychiatry. (2023) 22, no. 3, 394–412.
Taylor, David M, et al. The Maudsley Prescribing Tips in Psychiatry. 14th ed., John Wiley & Sons, 2021 pg 318-319.
