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Tuesday 20 January 2015

Why is Depression Becoming More Common: Some Likely Cultural Factors

In a recent post I pointed out that having an effective treatment for a disorder should have a positive impact on at least some epidemiological variables: prevalence, chronicity, disability – something. And yet relative to the 1950s, major depression is not on the run. It is becoming more common, there are more people on depression-related disability, it appears earlier in people’s lives, it seems more likely to recur than ever, and recovery between episodes is less complete than historical accounts would suggest.

Something’s going wrong.

Many, including Robert Whitaker (author of Anatomy of an Epidemic) suggest that our treatments themselves are producing much of the increase – and he outlines some fairly good research to support this point of view.

It’s likely, however, that multiple factors come into play – and some of these are societal factors. Today let’s look at some of these.

Physical fitness

We know that exercise is an effective treatment element for depression, and that poor physical fitness is a risk for future depression. Standardized population studies examining fitness over the decades are hard to come by, but indirect measures (the proportion of jobs that are sedentary, the decline in physical education in schools, the increase in childhood and adulthood obesity) support the limited direct data indicating a general decline in physical fitness from the 1950s to the present. If true, this should account for some of the increased incidence of depressive disorders and subclinical depression.


Overweight individuals are more likely to be depressed, but the direction of causality is open to question and likely bidirectional: obese individuals appear to be  at higher risk of developing depression, and mild to moderate depression appears to increase the likelihood of a person becoming overweight. As well, obesity may be a marker of physical activity, with individuals who are less active developing both increased body weight and reduced mood. Whether there is an independent relationship between obesity and the subsequent development of depression is at this point somewhat unclear.

Social Isolation

In his book Bowling Alone (2000), Robert Putnam describes the decline of participation by Americans (and citizens of other western nations) in organized social groups such as fraternal organizations, sports leagues, and so on. Humans are social animals, and isolation is a known risk factor for depression. Social contact has declined on almost every conceivable measure over the past 60 years, and it is likely that this has contributed to rates of depression. For example, the average number of people per household in the USA has declined from 3.3 in 1960 to 2.5 in 2013, and the number living alone has correspondingly increased. Loneliness tends to predict future depression levels more than the reverse (Cacioppo et al, 2010)

Screen Time

Increasing numbers of people point with pride to their lack of ownership of a television, or to their recent cancellation of cable services. Nevertheless, traditional television viewing remains at a US average of 34 hours per week (Nielson, 2013), to which we can add Internet use (26 hours per week on average) and computer gaming (averaging 13 hours per week for Americans 12 to 24; NPD Group 2010). These hours, which take up the majority of leisure time for most people, represent “empty hours” for fulfillment in the same way that soda pop provides “empty calories” without additional nutritional content.

News Media Saturation

In the 1960s, an era of almost unprecedented social change, assassinations, war, and upheaval, most people made do with a half-hour news broadcast that they might watch on an intermittent basis. In 2015 we have multiple competing 24-hour news channels, plus the constant Internet news feed providing information from virtually every news outlet on Earth. Many people report that they check the online news five or six times a day. The constant exposure to viscerally-reported tragedy and mayhem is likely to affect one’s mood (Dobelli, 2013), though controlled research is, as yet, lacking.

* * *

Those are just a few of the societal indicators that may be partly responsible for an increase in societal rates of depression. I have made no attempt to be comprehensive here; instead, I have just highlighted a few possible factors. Feel free to nominate your own in the comments feed.

No matter how many we collectively come up with, however, we are unlikely to explain the sheer magnitude of the leap in depression rates over the past 60 years. Other factors are coming into play as well – and in coming weeks we’ll consider some of the other influences.


Cacioppo, JT, Hawkley, LC, & Thisted, RA (2010) Perceived social isolation makes me sad: Five year cross-lagged analyses of loneliness and depressive symptomatology in the Chicago Health, Aging, and Social Relations Study. Psychology and Aging, 25, 453-463.

Dobelli, R (2013). News is bad for you – and giving up reading it will make you happier. The Guardian, April 12.

Nielsen Company (2013). Free to Move Between Screens: The Cross-Platform Report, March 2013. New York: The Neilson Company.

NPD Group (2010). Gamer Segmentation 2010 Report. May 2010.

Putnam, R (2000). Bowling Alone: The Collapse and Revival of American Community. New York: Simon & Schuster.

Whitaker, R (2010). Anatomy of an Epidemic. New York: Crown.

Online Course

Want to consider this subject? Consider taking our online course, What Causes Depression? The preview is below. For 60% off the regular fee of $50 USD, use coupon code “cause20” when you visit our host site, here.

We also have courses entitled UnDoing Depression, What Is Depression, Diagnosing Depression, Cognitive Behavioral Group Treatment of Depression, How to Buy Happiness, and Breathing Made Easy. For the full list with previews and substantial discounts, visit us at the Courses page of the Changeways Clinic website.

Tuesday 13 January 2015

"Science" in Court: Study 329, Paxil, and Depressed Adolescents

Science: Dead, but not entirely forgotten.
We hear a great deal about the problems facing modern psychopharmacology – allegations of bias, the distortions of results, poor research design, and adverse effects being underplayed.

These issues are all on display in the microcosm of a single study: the notorious “Study 329” undertaken by GlaxoSmithKline to investigate the usefulness of paroxetine (Paxil), over which it then held patent, for depression in children and adolescents. The complete text of the published article can be found here.

The study was carried out between 1994 and 1997, and was ultimately published in the Journal of the American Academy of Child and Adolescent Psychiatry in 2001.

The subjects were 275 12- to 18-year-old patients suffering from major depressive disorder (winnowed from an initial screening of 425 potential subjects). These were randomly assigned to one of three conditions: paroxetine, imipramine (an older tricyclic medication not normally recommended for use with children), or placebo (an inert dummy pill). Both patients and providers were blind to the treatment being administered, as is standard practice.

Like most medication trials, the duration was limited – in this case, the treatment phase was just 8 weeks. Many of the concerns about antidepressant medication involve what happens over the longer term, but this study was not designed to examine longer-term treatment gains or adverse events.

So what happened?

Let’s jump to the conclusion in the study abstract: “Paroxetine is generally well tolerated and effective for major depression in adolescents.” Well this sounds great. If you are a busy physician reading the study abstract and not looking any closer, the conclusion looks clear.

Internal letters (click to see a complete copy) were more muted: “As you will know, the results of the studies were disappointing in that we did not reach statistical significance on the primary end points and thus the data do not support a label claim for the treatment of Adolescent Depression.”

The aim of the memo in question is spelled out quite clearly:

To effectively manage the dissemination of these data in order to minimize any potential negative commercial impact…. It would be commercially unacceptable to include a statement that efficacy had not been demonstrated, as this would undermine the profile of paroxetine.”

(Ensuring the safety of the tens of thousands of adolescents likely to be prescribed paroxetine is, unaccountably, not mentioned. Maybe I missed it.)

Contrast this assessment with subsequent marketing information sent to GSK’s sales representatives: “This ‘cutting edge,’ landmark study is the first to compare efficacy of an SSRI and a TCA with placebo in the treatment of major depression in adolescents. Paxil demonstrates REMARKABLE Efficacy and Safety in the treatment of adolescent depression.” (quotation taken from the charge of the US District Court in Massachusetts in USA v GlaxoSmithKline).

The Actual Results

Let’s go back and look at what actually happened in this study.

There were two primary outcomes defined at the outset of the trial.

  1. A treatment response in which participants would either achieve a Hamilton Rating Scale for Depression (HAM-D) score of 8 or less, OR a reduction from their initial HAM-D score of 50% or greater. Outcome: Neither medication achieved a significant difference from the placebo group.
  2. A change in the total HAM-D score from the pre-treatment to the end of the trial. Outcome: Neither medication demonstrated statistically significant superiority to placebo.

There were five secondary outcomes that were also defined at the outset of the trial. Statistical significance was achieved on none of these.

According to the Department of Justice, investigators defined an additional four secondary endpoints later in the study – but before the results were “unblinded.” (This means that they defined the endpoints before knowing the results – had they done so only once they had the results in hand, the breach would have been worse.) Statistical significance was achieved on several of these later-defined endpoints – though their relevance to actual improved quality of life for patients is open to question.

The eventual article defines the two primary endpoints and lists five secondary endpoints rather than nine – including three of the later-defined endpoints that achieved statistical significance. An accompanying table gives 8 endpoints (2 primary plus 6 secondary).

Aside: The deletion of nonsignificant endpoints is important in studies like this, because as the number of endpoints increases, the likelihood of achieving significance on some of them by random chance increases as well. Using a .05 threshold for significance, one in every 20 variables can turn out significant by chance. Most of the significant outcomes in this study (on only later-defined secondary endpoints, no less) are not impressively so. Performing a standard statistical correction for the number of comparisons would most likely have reduced the number of significant differences even further.

What about adverse events?

Consider one of the two sentences from the study’s short conclusion: “The findings of this study provide evidence of the efficacy and safety of the SSRI, paroxetine, in the treatment of adolescent depression.”

Well, that seems clear enough. But let’s go back to the actual outcomes.

The imipramine group had an alarming number of cardiovascular side effects – in keeping with past results indicating problems with tricyclic antidepressants for younger patients.

Many of the long list of side effects were similar between paroxetine and placebo, though somnolence affected 17.2% of the paroxetine group and 3.4% of the placebo group, and tremour affected 10.8% vs 2.3%. Not disasters, really.

But further down in the “Adverse Effects” section is what we’re really looking for: “serious adverse effects.” Based on what the study concludes, we might guess that these were minimal. But no. The rate of these events was 11.8% in the paroxetine group versus 2.3% in the placebo group. (Keep in mind that providers did not know which drug patients were taking – any medical event occurring during those 8 weeks might be due to the drug or to coincidence.)

What were the paroxetine group’s adverse effects? Emotional lability (including suicidal ideation or gesture) – 5 patients, conduct problems or hostility – 2, symptoms suggestive of mania – 1, worsening depression – 2, and headache upon discontinuation – 1. It appears that no patient in the placebo group required hospitalization, but seven in the paroxetine group did.

Keep in mind that we often give antidepressants with two big goals in mind (in addition to the obvious one of reducing depression - which Paxil failed to do in any impressive way):

  1. Let’s keep this person’s problem within manageable levels so they don’t have to go into hospital.
  2. Let’s treat their mood problem to reduce the risk of suicide.

To see a higher rate of both suicidal ideation and hospitalization for a drug likely to be prescribed to do the opposite is a big warning sign.

Remarkably, the study report states (apparently not anticipating raised eyebrows), “Of the 11 patients [suffering serious adverse effects in the paroxetine group], only headache (1 patient) was considered by the treating investigator to be related to paroxetine treatment.” Later in the discussion of results comes a remarkable statement: “Because these serious adverse effects were judged by the investigator to be related to treatment in only 4 patients (paroxetine, 1; imipramine, 2; placebo, 1), causality cannot be determined conclusively.” Readers may be forgiven if they missed the bulletin in which investigators' opinions were elevated to the level of outcome data.

Even more remarkable is an allegation included in the Department of Justice charge: “An earlier draft of the article stated that of the 11 SAEs experienced by Paxil patients, ‘worsening depression, emotional lability, headache, and hostility WERE (emphasis added) considered related or possibly related to treatment.” The change in the treating investigator’s mind apparently occurred during the editing process in the final preparation of the article. If true (and I'm not clear whether this was firmly established), this would be outright fraud.

Studies 377 and 701

Needless to say, not all of GSK’s eggs were placed in one basket. There were others.

Study 377 looked at Paxil versus placebo in 13- to 18-year-olds and, according to the Department of Justice charge “failed to demonstrate efficacy on any of the primary or secondary endpoints.”

Study 701 looked at paroxetine versus placebo in seven- to seventeen-year-olds. It too failed to reach significance on any of the primary or secondary endpoints.

It would be fun to look at the spin placed on these results in the final publications. But of course there weren’t any. As the internal GSK memo tartly states, “There are no plans to publish data from Study 377.”

This is an illustration of a common problem in psychopharmacology. Physicians are advised to keep up to date on the science regarding the treatments they use, and they do so by reading journal publications. But the journals have not, in the past, published all of the data. Positive results tend to find their way into print, negative ones are hidden under the mat. The result is that almost any medication looks good based on the published literature.

Recently there has been a push to correct the problem. Teams launching a trial are required to declare a study prior to starting out, and then must publish regardless of the results. This is a positive step, though how it will play out in practice remains to be seen.

USA v GlaxoSmithKline

The United States attorney charged GSK with misbranding its medications (including Paxil, Wellbutrin, and Avandia), and with failure to report data to the Food and Drug Administration. The complete charge can be read in its entirety here.

Discussion of the data on Paxil begins on page 5.

Discussion of the subsequent writing of the positive paper on Study 329 appears on page 9-11.

The subsequent marketing of Paxil by its sales representatives to physicians is discussed on pages 11-12.

Discussion of the safety data for adolescents appears on page 13-14, including the FDA decision to impose a black box warning on antidepressants regarding the risk of increased suicidality.

For those still imagining that the method used to encourage prescribing practices is the impartial reporting of science, the material on page 14 to 19 should prove to be a bitter but necessary tonic. (If you like to fish, sail, travel, take balloon rides, and be paid an honorarium to do so, this shows how to go about it.) The only surprise to those of us in healthcare is that such practices should attract notice at all, because they are hardly limited to the drugs in the court case.

And the result? Here is the 2012 press release on the $3 billion settlement arising from the GSK guilty plea.

It would be nice to view Study 329 as an aberrant low point in the field of psychopharmacology and medication marketing. Regrettably, it does not appear to be.

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In addition, our clinic has developed a cognitive behavioral guide to self-care for depression. Though not a substitute for professional face-to-face care, UnDoing Depression may be a useful adjunct to your efforts.  The preview is below. For 50% off the regular fee of $140 USD, use coupon code “changeways70” when you visit our host site, here.

We also have courses for professionals and for the public entitled What Is Depression, What Causes Depression, Diagnosing Depression, Cognitive Behavioral Group Treatment of Depression, How to Buy Happiness, and Breathing Made Easy. For the full list with previews and substantial discounts, visit us at the Courses page of the Changeways Clinic website.

Tuesday 6 January 2015

Why is Depression Incidence Increasing?

A happier time?
As discussed in last week’s post, since 1956 (when the first of the tricyclic antidepressants was released) the rates of depression in the general population have skyrocketed. Depression has become widespread where it was formerly rare, recurrences have become more common, inter-episode recovery has declined, and long-term disability has increased.

Some of these changes can be argued about to an extent. Some cases may not have been found in the 1950s. Chronicity may have been inadequately monitored or reported. The lack of disability insurance may have forced the disabled into work, or into the back bedroom of the house, where they might go uncounted.

These and related observations might account for the apparent rise of depression if the numbers were in any way similar, but they are not. Estimates of depression prevalence are between 10 and 1000 times as high today as they were in the 1950s. No failure of measurement can account for an increase that large. Either the disorder is trivial and therefore easily missed (and unnecessary to treat), or it is significant and at least somewhat obvious to caregivers and families.

(Note: Both of those bracketing numbers are extremes – I have seen no reports that would suggest depression is as infrequent as 10 times the 1950s rates, and the upper figure seems to be a comparison of a 1950s-era point prevalence estimate – 100 per million - with the modern lifetime incidence estimate of 10%, or 100,000 per million.)

If you raise this issue at a dinner party, do so with stopwatch in hand. Count the seconds until someone says “Life is so much more stressful now than in the 1950s.” Observe as they sit back, satisfied that the question need be given no further consideration. Even clinicians offer this all-too-pat explanation.

The speed with which we discard the notion that something else might be happening is surprising, and suggests discomfort with the topic. “If I look inside that cave I might find something unpleasant. So let’s just pretend it’s not there.” Mental health services, being so expensive, must be effective. So if depression has increased, it must be due to external forces. If we weren’t trying our best, surely they would be even higher.

Comparing 1956 to 2015

Nostalgia is almost always rose-tinted. A friend once expressed the wish that he lived in 1800s-era England. He was somewhat put out when I suggested that at his present age he would most likely be dead, and that perhaps his imagined version of Dickensian London was overly cheerful.

Rather than trying to compare the present day with the imagined past, let’s consider two concurrent societies: One with the living conditions of 2015, and a bordering nation with the conditions of 1956. In this thought experiment we will assume that dispassionate aliens have just landed, and we present them with a task: Examine the conditions of each society, then guess which one has the higher rate of clinical depression. For argument’s sake, I’ll use Canadian data for the example.

  • Life expectancy. 1956: 68; 2015: 80. Living on one side of the border confers an average of 12 additional years of life.
  • Income.  Higher in 2015 than 1956, adjusted for inflation, with a vastly increased array of products and entertainments available.
  • Recent war. 1956 is 12 years out of a world war that traumatized much of the population; there are significant fears of an impending nuclear exchange. 2015 has a recent military commitment in Afghanistan participated in by a far smaller proportion of the population.
  • Universal healthcare. 1956: Not in most provinces; illness runs a significant risk of bankrupting a family. 2015: Yes, plus extended health benefits available through most employers.
  • Childhood mortality. 1956 32.6/1000 (from 1956-1960 data); 2015: 6.1/1000 (estimate from 2011 data). Children in 1956 routinely die from a multitude of communicable diseases ranging from diphtheria to polio. Parents suffer realistic fears that one or more of their children will not reach adulthood. In 2015, fears of communicable illness have waned sufficiently that many give more attention to discredited concerns about vaccines, and see little reason to have their children vaccinated.
  • Status of nonwhite, nonheterosexual, disabled, and female populations. Varies by group, but in virtually all cases worse in 1956 than 2015.

This is, admittedly, a highly selective set of factors on which to compare two cultures. It would be easy to generate dozens more, and on some of them 1956 would do better than 2015. Insert any variables you like.

Then pose the question to the observers: “Which of these two cultures would you guess has the higher rate of clinical depression?” 

Once we set aside nostalgia, it’s difficult to escape the conclusion that 1956 should have a somewhat higher incidence than 2015.

Perhaps you disagree, feeling that the two might be judged equal once all positives and negatives are tallied, or that 2015, with its environmental concerns and focus on terrorism, would be judged the harsher world. Fine. But would our impartial observers conclude that the rate of depression should be 10 times as high on one side of our hypothetical border than the other? A hundred times? Unlikely.

Something else must surely be going on, for our efforts to conquer depression have failed this badly.

Treatment Penetration

Another explanation that is frequently offered for the increase in depression in our culture is that too few sufferers seek help. Only half of people with depression tell their doctor, so this myth goes, and only half of those are given treatment.

This is nonsense.

More Americans currently take antidepressant medication (11%) than are thought likely to have a major depressive episode in their lifetime (10% by most estimates). Figures in Canada and other developed economies are similar. “From 1988-94 to 2005-08, the rate of antidepressant use in the United States among all ages increased nearly 400%” (Pratt, Brody, & Gu, 2011). One study found that 19% of British Columbia women were prescribed an antidepressant in 2003.

The problem is clearly not the failure of antidepressant treatment to reach those who need it. Indeed, over-prescription appears to be a significantly greater problem than under-prescription.

So what’s happening?

It’s not entirely clear at this time why depression rates have risen so dramatically. In all likelihood, there are multiple factors at play.

One possibility raised by many – and summarized by Robert Whitaker, in his book Anatomy of an Epidemic - is that pharmacological treatment itself may be one of the prime culprits, despite clearly helping some of the people who take it.

This line of reasoning contrasts short-term improvement (which is usually the variable examined in medication outcome trials) with long-term outcomes (such as chronicity, recurrence, and disability). The latter are examined much less often than the former. We have tended to assume that short-term gains predict sunny long-term outcomes, but it turns out that this may not be the case. More on this in another post.


Pratt, LA, Brody, DJ, & Gu, Q (2011) Antidepressant use in persons aged 12 and over: United States, 2005-2008. National Center for Health Statistics Data Brief, Number 76, October 2011.

Whitaker, R. (2010). Anatomy of an epidemic. New York: Crown.

Online Course

Want to consider this subject? Consider taking our online course, What Causes Depression? The preview is below. For 60% off the regular fee of $50 USD, use coupon code “cause20” when you visit our host site, here.

We also have courses entitled UnDoing Depression, What Is Depression, Diagnosing Depression, Cognitive Behavioral Group Treatment of Depression, How to Buy Happiness, and Breathing Made Easy. For the full list with previews and substantial discounts, visit us at the Courses page of the Changeways Clinic website.