Do Higher Doses of Antidepressants Work Better?

It is common practice in psychiatry to increase the dose of an antidepressant if the standard dose is not helping enough.  Sometimes doses are increased before even finding out if the lower dose is working. 

But it is interesting to consider evidence that higher doses actually do not necessarily work better:

Ruhé et al. (2009-2010) have published research on this issue, and conclude that SSRI dose increases do not improve effectiveness.  Their explanation for this is quite simple:  serotonin receptors are already well-occupied at standard doses, and this does not change with dose increases:  
http://www.ncbi.nlm.nih.gov/pubmed/18830236
http://www.ncbi.nlm.nih.gov/pubmed/20862644

In general, it is indeed interesting to see scanty evidence that increasing antidepressant doses lead to improved effectiveness, even for treatment-resistant cases.  

This issue came to my attention upon reading Lam's recent article about using light therapy to treat non-seasonal depression   ( http://www.ncbi.nlm.nih.gov/pubmed/26580307).  Their medication groups used only 20 mg of fluoxetine, without the possibility of increasing the dose.  They cited some old, dated references to support this, such as Altamura et al (1988), and  Beasley (1990):
http://www.ncbi.nlm.nih.gov/pubmed/2196623 

 http://www.ncbi.nlm.nih.gov/pubmed/3074862

 
A better, more recent article reviewing antidepressant dose vs effectiveness is by Berney (2006):
http://www.ncbi.nlm.nih.gov/pubmed/16156383


In many studies, higher doses may appear to work better, mainly because the dose was increased before the lower dose had a chance to work fully.   The lower dose may well have worked just as well as the higher dose.  Controlled studies comparing different doses do not support the belief that higher doses work better.

So it should not be routine practice to increase antidepressant doses beyond a standard "full dose" which is usually one tablet or capsule daily.    In many cases, the different dosage regimes are likely to be equivalent.  It is relevant to consider that higher doses mainly benefit the pharmaceutical companies, since they are selling more product despite the effectiveness being the same.  Therefore, presentations of research data about antidepressant effectiveness may be biased in favour of higher doses.  An extremely common research design in antidepressant studies is to have "flexible dosing," usually leading to the antidepressant group averaging about twice the standard dose in the end.  This design, even when treatment effects are shown, biases the reader to have the specious conclusion that higher doses are better.

However, there are certainly many individual case reports of higher doses being more useful.  So dose increases may have a role in some cases.

The key point is to question dose increases as a reflexive, routine management strategy for inadequate antidepressant effects.  Alternative strategies include giving the lower dose a longer try, switching to something else, or using some form of augmentation.

Addendum:

Just days after posting this, I see there is a new meta-analysis by Jakubovski et al. in The American Journal of Psychiatry (173:2,pp. 174-183) which suggests that SSRI antidepressants do actually work slightly better at higher doses, peaking at 2.5 times the standard dose (e.g. 50 mg fluoxetine).   They admit that the data show a trade-off between slight improved effectiveness at higher doses, but accompanied by worsened tolerability. 

Yet, it is important to consider that higher doses could reflect a greater placebo effect; some of the research about active placebos show that agents which cause more side effects are likely to have a larger impact on symptoms than inert placebos.  Because antidepressants at higher doses have more side effects, there would be more of this "active placebo" effect.  See my previous post on this subject: http://garthkroeker.blogspot.ca/2009/03/active-placebos.html


It's hard to know what to make of this, other than to probably remain open-minded about the issue.  I think that a better study design for this type of issue is to look at dose comparisons within individual clinical trials, rather than to amass data meta-analytically.   Active placebo comparison groups would also be useful.  For example, agents which would cause very mild side-effects could be used instead of a totally inert placebo, so as to improve the blinding of the studies.    In many individual clinical trials of antidepressants (both new and old) which compare doses or dose ranges within the studies themselves, there are no significant differences in effectiveness.

Another issue, which the authors point out, is that most antidepressant studies have strict inclusion criteria which usually do not match the type of cases one would tend to see clinically most often.  Many studies require a major depressive disorder diagnosis, with limited comorbidities allowed, and with limited past treatment trials, etc.

Meanwhile, it remains reasonable to give a baseline dose of antidepressants an adequate length of time to work, without reflexively increasing the dose on a routine basis.   Dose increases remain an option, with some evidence-based support, but switching or augmentation could often be preferred, depending on patient preference and side-effects. 

Mental Health Care Organization & Advocacy

A grave problem in the world today is the lack of timely access to mental health care.

The roots of this problem are located in basic societal factors, such as poverty, political oppression, crime, and lack of educational opportunity. 


These social factors influence the prevalence, severity, and prognosis of mental health problems.  Mental health problems still occur frequently, even in affluent, safe, free environments, but it is important in health care to address the core societal needs as the first, most important, and most powerful rung of care.


These issues are very "political," since changes in poverty and social freedoms, etc. require the involvement of a community's leadership on all levels.

What is the role of the existing community of therapists and other mental health workers to improve quality and timely access to mental health care?

A common pathway nowadays is to employ a type of  "corporate" model to improve efficiency.  In industry, it is very clear that an assembly line is much more efficient, to produce the largest quantity of goods, with good quality control, in a very consistent, standardized way, with the least possible amount of money and time.    Such an approach requires teams of workers, supervised by managers, with each individual worker having a particular area of specialization.

In many corporations or businesses--such as banks--there are also regular efforts to evaluate employee performance, so as to enhance productivity.   There may be performance reviews done by management, or perhaps quotas to meet, or quantified analysis of productivity which is then reviewed regularly. 

The mental health analogy of an assembly line would be a type of corporate structure, with various members of a team involved in care.  So one might deal with a clerical worker to organize appointment times, a social worker, an occupational therapist, a nurse, a primary care physician, a clinical counselor, and a psychiatrist.  Even prior to entering this structure, one could deal with friends, family, peer support volunteers, or in a university setting it could be professors, residence workers, etc.

In order for such a system, with multiple rungs of care involved, to work smoothly and helpfully, there would need to be a sense of warm, harmonious collaboration, allowing the experience of being supported by a community.

The risk of such a system, particularly if it is not running smoothly, is that a person could feel like their care was divided or pigeon-holed.  It could indeed feel like interacting with a corporation, in the negative sense of the word.  (For a particularly critical set of insights about this, I am reminded of the documentary book and film by UBC law professor Joel Bakan, entitled The corporation). 

Performance reviews often could lead to a dramatic reduction in morale in an organization, even if the short-term goal of increased "productivity" is reached.  Generally it is stressful for workers to feel scrutinized in a hierarchical system.  Another consequence of a highly monitored work environment could be subtle changes in the pattern of practice:  workers may avoid more difficult, chronic cases, since these would be more likely to lead to negative "productivity ratings."   Creative initiatives in the workplace could become inhibited, since it would be "safer" from a productivity point of view to stick with established practices.  Also, this type of environment would lead to a type of natural selection process, in which workers with a greater tolerance for such scrutiny and stress would become more abundant in the worker population.  Those workers with less tolerance for this would become less prevalent in this system, due to burnout, and due to such a person not wanting to apply for work in such a system.  

In some parts of the world, psychiatry is reserved only for "medication consultation," thus leading to atrophy of clinical skills among psychiatrists, as well as overuse of medications, all in rushed, highly medicalized brief appointments. 


While I applaud efforts to improve efficiency, I am aware of serious risks.

I see a rise in bureaucratic activities in health care.  I see more people, including talented, warm-hearted clinicians, spending their time in front of computers, attending meetings, doing research, or doing some kind of administrative task, instead of dealing on a personal level with people in need.   More people are hired, while a smaller proportion of workers' time is spent helping people on a personal level. 

Some types of bureaucracy are unavoidable, and necessary for excellence.  For example, in hi-tech manufacturing, we absolutely must cooperate with specialists, many of whom across the world, to share the task of creating something amazing or world-changing.  The creation of a modern computer or airplane requires hundreds of highly specialized steps, starting from the mining and processing of rare earth metals, to metallurgical processing, to specialized manufacturing of countless components, to involvement of mathematicians, physicists, engineers, and other designers.  The finances for such projects need to be organized by people with expertise in commerce and business.

Mental health care does have some aspects in common with airplane manufacturing!    But in many ways I believe that it is quite different.

Most patients I see have not really benefited from bureaucratic involvements, but rather have been stressed by them.   Hi-tech therapeutic "tools" have often been tried, ranging from trials of "manualized" therapy to computer apps, to sophisticated combinations of medications.    

I do not claim that such "tools" are unimportant (actually I think many of them are interesting, clever, imaginative, and uniquely helpful for many),  but rather that they must not become the sole focus of a network of health care,  that is becoming increasingly impersonal, bureaucratized and corporatized.

The foundations of mental health care are personal empowerment, through economic and educational freedom, followed by the opportunity to have a reliable, stable personal relationship with a helping figure if desired.   Physical treatments should be available but not pushed upon people as a default approach, or because personal care was not an option. 

If the system is preoccupied with technical and bureaucratic aspects of care, at the expense of personal relationships, then I believe we are facing a steep decline in the quality and availability of mental health care for those most in need.

A particularly insidious part of this problem would be that an assembly-line type of mental health care bureaucracy could most certainly allow more people to be seen, to shorten wait lists, etc.  This could lead an external observer to assume that the system had improved.   But the decline in quality -- which could risk becoming part of a cultural norm, just as fast-food restaurants or donut shops have become a community norm -- may not be noticed or addressed.  


In order to protect the quality of mental health care, I encourage those who have had a positive experience of their own care to be sure to speak up, to offer feedback and advocacy if possible, so as to guide the system towards providing similar positive care experiences for others.  


Personal care is expensive to society, in terms of time and money.  Bureaucratic care is undoubtedly less expensive, at least in a shorter-term view.   At present, many people in dire need have no care at all.  Arguably, economically efficient bureaucratic care is preferable to no care at all.

But another option is for our society to invest much more attention and time to offer high-quality, personal care for everyone.   For this to occur, or to continue, it is likely that advocacy is needed.

Reference:

Bakan, J. (2004). The corporation: the pathological pursuit of power and profit. New York: Free P.