Antidepressant Efficacy: Hard to Prove

Antidepressants have not fared particularly well in clinical trials to determine efficacy. Placebo effect has gotten stronger over the years, resulting in many expensive failures of late-stage (Phase III) drug trials, with the result that most major drug makers have halted R&D programs aimed at developing new psychiatric drugs. Many of today's most popular drugs for depression barely achieved efficacy 30 years ago; if they had to jump through the same FDA hurdles today, most wouldn't make it.

The following table, from a 2003 Neuropsychopharmacology paper by Khan et al., shows the results of fixed-dose clinical trials (done for FDA approval) for a variety of antidepressants: fluoxetine (Prozac), nefazadone (Serzone), venlafaxine (Effexor), sertraline (Zoloft), bupropion (Wellbutrin), and citalopram (Celexa). Note that Serzone has since been pulled from the market over liver toxicity concerns. Trials in which the drug (at the dose shown) was superior to placebo are shown in bold. Remarkably, only a third of trials showed the drugs to be better than placebo.

		Placebo	Antidepressant
Antidepressant: protocol	Duration of trial (weeks)	% symptom reduction	% symptom reduction	Dose (mg/day)
1. Fluoxetine: 62	6	23.5	39.7	20
			39.8	40
			29.8	60
2. Nefazadone: 03AOA-003	6	26.3	32.5	50–250
			43.0	500
3. Venlafaxine: 600A-203	6	26.5	42.7	75
			45.8	150–225
			42.2	300–375
4. Sertraline: 103	6	30.0	42.7	50
			39.4	100
			35.8	200
5. Bupropion: 203	8	34.9	43.6	300
6. Bupropion: 205	8	35.5	38.1	300
			38.4	400
7. Nefazadone: 030A2–0007	6	37.1	51.0	200
			42.1	300
8. Mirtazapine: 003–008	6	37.2	29.2	15
			26.7	30
			32.0	60
9. Venlafaxine: 600A-313	6	37.4	42.6	50–75
			46.1	150–200
10. Citalopram: 91206	6	37.8	40.6	20
			50.0	40
			49.4	60
11. Nefazadone: 03AOA-004A	6	37.9	35.8	150–300
			40.3	300–600
12. Nefazadone: 03AOA-004B	6	38.0	40.2	100–300
			50.0	300–600
13. Bupropion: 212	8	41.0	45.5	300
14. Citalopram: 89303	6	44.7	45.7	40
15. Venlafaxine ER: 367	8	49.2	57.8	20
			58.9	75
			53.9	150

How, then, did FDA decide to approve the drugs? Fixed-dose trials are not the only kind of trials used in drug approval. The drug makers also submit flexible-dose trials. Those are successful around 60% of the time. (See the Khan paper for data.)

Fixed-dose trials are typically done to establish dose-response relationships. Since weaker doses might not be as efficacious, it stands to reason that fixed-dose trials (which can be weighed down by weak-dose results) should fare worse than flexible-dose trials in terms of establishing efficacy. In theory, at least. In reality, that's not what Khan et al. found. When they looked at symptom reduction as a function of dose, they were unable to demonstrate a clear relationship ("paradoxically," in the investigators' words). Dose doesn't seem to matter much.

Looking at overall results, the average improvement in patient HAMD score was 35.8% for those who received placebo and 42.2% for those who got an antidepressant. One interpretation of this is that 85% (35.8 divided by 42.4) of the benefit of the drugs is due to placebo effect. But it's also possible that the only thing we're seeing here, in any of the results, is placebo effect. The greater "response" on drugs may be due to breaking of blind, as drug-takers realize (when side effects start to kick in) that they're not in the placebo group and begin thinking they're taking something powerful (when really it's just a different kind of placebo). This would also explain why dosage doesn't matter.

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Can Antidepressants Make You Bipolar?

Bipolar disorder is a spectrum disorder characterized by at least one manic or mixed episode, alternating (typically) with depressive episodes. It conforms to Kraepelin's original concept of manic-depressive illness, which can include psychosis symptoms during mood episodes. In bipolar I, you see swings between manic and depressive episodes; in bipolar II disorder the individual never experiences a full manic episode but instead exhibits less severe hypomania (which has the expansiveness of mania but lacks the delusional grandiosity). There's also a somewhat controversial diagnosis of Cyclothymic Disorder, which refers to a serious lability of mood that (for whatever reason) fails to meet the diagnostic requirements of bipolar.

On Showtime's Homeland, Claire Danes (left) played a bipolar CIA agent.
(Mandy Pitinkin, right, played opposite her as a CIA higher-up.)

Despite bipolar's depiction in modern culture as being somewhat common, it's actually quite rare. Bipolar disorder occurs naturally (in the U.S.) at a lifetime rate of 4%. That figure turns out to be quite a bit higher than the condition's actual worlwide prevalence (rate of actual occurrence at any given moment). The World Mental Health Survey initiative found a prevalence of bipolar II in the population of eleven countries to be 0.4%, making it less common than schizophrenia. The prevalence rates of bipolar I and II are thought to be comparable. In the U.S, each occurs with a prevalence of about 1%.

The Diagnostic and Statistical Manual of Mental Disorders (5th Ed.), in its formal criteria for bipolar, discounts mania as mania (or as hypomania) if it's induced by drugs, which is extraordinarily convenient, in that antidepressant drugs can and do cause hypomania in some people. I say "convenient" because the drug companies are keenly interested in dispelling the notion that (unipolar) depressed patients who start taking antidepressants are often, in so doing, converted to bipolar patients, which is exactly what does happen at several times the spontaneous rate.

In a literature review of 51 studies involving nearly 100,000 patients with MDD without a history of mania or hypomania who were treated with an antidepressant, Baldessarini et al. (2013) found bipolar mood switching occurred in 8.2% of patients within an average of 2.4 years of treatment. They also said: "We considered 12 studies of patients initially thought to have unipolar MDD who required a new diagnosis of bipolar disorder, usually with verification by occurrence of spontaneous mania or hypomania. Such diagnostic changes occurred in 3.3% within 5.4 years, or 5.6 times less than the rate of mood switching with antidepressants."

What it means is that if you go to your doctor with major depressive disorder (unipolar depression) and start taking antidepressants, there's an 8.2% chance you'll be bipolar within 2.4 years. Some people react to antidepressants by going manic or hypomanic. It may not happen in the majority of cases, but it is a significant chance, and the longer you're on antidepressants, the greater the chance of a changeover to bipolar.

From personal experience, I can tell you that if your daily routine includes coffee in the morning and alcohol at night, you stand a much better chance of avoiding the bipolar switch if you cut alcohol out of your life completely and keep coffee and other stimulants under control. Coffee and alcohol are cyclothymia triggers (potentially). You want to moderate their effects.

What happens if you do experience mania? Is there a known-good way to treat it? Actually, there is. It's called lithium carbonate, and it's one of the best proven, least expensive anti-mania treatments money can buy. It's also fast-acting and can be taken "PRN" (which means as needed), although it's rarely prescribed that way. The problem with lithium is that today's doctors are using 50-year-old dosing recommendations that often result in a patient taking toxic amounts of the stuff. A typical dosing regimen is 450 mg two to three times a day. That kind of dose will make you toxic in a couple of weeks, but unfortunately, there are few modern studies involving lower-dose lithium. One such study that's worth considering is Alevizos et al. (2012), which looked at the response to adjunctive low-dose lithium in 47 severely depressed patients who failed to respond to venlafaxine (Effexor) alone. Said the researchers: "After 5 weeks of augmentation, 51% of the patients were rated as 'much' or 'very much' improved. Bipolar patients showed a better response than unipolar (64.3% vs 45.5%, p<0.038). Most patients (76%) showed a rapid response (up tp 7 days)."

Two things need to be mentioned with regard to the Alezivos study. First, there was no placebo control arm, hence the results await validation by a properly controlled, properly blinded study. Secondly, "low dose" here meant 300 to 450 mg per patient per day (corresponding to about 5 mg/kg), which is still a high dose. Modern medical science still hasn't wrapped its head around the idea that you can benefit from low doses of lithium, even though we have tantalizing evidence (see, for example, this study; there are others) that micromolar concentrations of lithium in tap water can prevent suicide.

Much of the information in this post was taken from a 110,000-word book I'm writing on mental illness. To follow the book's progress, add your name to the mailing list and return to this blog often. Thanks!

Can Antidepressants Make You More Depressed?

Antidepressants of the SSRI and SNRI types are very widely prescribed now, sometimes off-label, sometimes for milder depression symptoms, often by family doctors rather than psychiatrists. Anyone who tries one of these drugs should be alert to possible adverse effects, one of which is that they can make you feel worse rather than better, at least initially, if not longer term.

All of these drugs now come with a black box warning (so-called because there's generally a black outline around the warning, in the printed instructions that come with the medication). The one for Effexor says:

Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, teens, and young adults. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. EFFEXOR XR® (venlafaxine HCI) is not approved for use in children and teens.

Some mention age 24 as the upper cutoff for the warning. Don't be misled into thinking there's something magical about a particular age limit. The 23-year-old brain is not that different from the 33-year-old brain. It's important to understand that younger people, because they have less life experience, tend also to have less practice dealing with adversity, and thus have a smaller repertoire of coping skills; plus they tend to maximize ("catastrophize") adversity, or at least teens do. Therefore it's not surprising that people in younger age groups tend to reach for the "suicide" button a little quicker than the rest of us.

In the book I'm writing on mental illness, I devote a chapter to suicide. It's a complicated subject, but one of the main things to understand about it is that, across most cultures, suicide risk increases with age. The following graph applies to the U.S., but many other countries follow this pattern.

Suicide is also much more of a problem in men than in women. (China is the only country is which women outperform men here.) In the U.S., men complete three times more suicides than women (on a rate-per-100,000-people basis), with elderly white men particularly at risk.

But back to the black box warnings: It's not that the young-adult brain responds to these drugs (SSRIs, SNRIs) in some physiologically unique way. Rather, it's that a younger person is more prone to play the suicide card to begin with; young people make more suicide attempts than older people (but not more completed attempts). It's much more their style of coping, than for older adults. A mature adult is likely to consider a range of other options first, before reaching for the suicide button.

Many people in the medical community have argued against the black box warnings, basically alleging that untreated depression is more likely to kill you than taking the meds. (For more on the controversy, see this psychiatrist's blog. Also see this article in the New England Journal of Medicine.) The black box warnings are there for a reason, though. These drugs can make you feel worse. The Cochrane Collaboration (a respected group that specializes in meta-analyses) did its own review of the literature surrounding the use of antidepressants in young people. This is what they found:

We judged none of these trials to be at low risk of bias, with limited information about many aspects of risk of bias, high drop out rates and issues regarding measurement instruments and the clinical usefulness of outcomes, which were often variously defined across trials. Overall, there was evidence that those treated with an antidepressant had lower depression severity scores and higher rates of response/remission than those on placebo. However, the size of these effects was small with a reduction in depression symptoms of 3.51 on a scale from 17 to 113 (14 trials; N = 2490; MD -3.51; 95% confidence interval (CI) -4.55 to -2.47). Remission rates increased from 380 per 1000 to 448 per 1000 for those treated with an antidepressant. There was evidence of an increased risk (58%) of suicide-related outcome for those on antidepressants compared with a placebo (17 trials; N = 3229; RR 1.58; 95% CI 1.02 to 2.45). This equates to an increased risk in a group with a median baseline risk from 25 in 1000 to 40 in 1000. Where rates of adverse events were reported, this was higher for those prescribed an antidepressant.

(Emphasis added.) The risk of a reported suicide-related outcome increased 58%; of course, we can't know how many people simply felt worse and didn't report it. It's worth bearing in mind that Adverse Drug Events (ADEs) involving psychotropic medications send 90,000 people a year to the emergency room, in the U.S. Of that number, 25,000+ ADEs involve antidepressants.

A relatively large (N=15390) study of antidepressant use in patients aged 10 to 19 in Finland found, interestingly, that among antidepressant users (relative to non-users), suicide attempts went up 39%, but completed suicides went down 32%. How are we to interpret this seemingly contradictory result? It's not that hard. First, the increase in suicide attempts clearly shows that these drugs can make you want to kill yourself. But if you reach for the bottle of (antidepressant) pills as a way to "end it," you're far less likely to kill yourself than if you reached for a gun (or decided to hang yourself, or jump from a building). And this, indeed, is the explanation offered by the study's authors.

Comforted? Neither am I.

It's not hard to find anecdotal accounts online of people who took an antidepressant and tried to commit suicide. Perhaps the best known recent case was the death of Robin Williams, who was taking Remeron and Seroquel at the time he committed suicide. It's impossible to know for sure if the drugs were causally involved in Williams's death. (He had just started on Seroquel, a week earlier.) But we do know that the relative incidence of self-harm events (across all age groups) is greater following the prescription of SSRIs than following the prescription of tricyclic antidepressants, and this, I think, gets to the key issue. The newer drugs can sometimes (in some people) cause depression symptoms to get worse, and it's not just a phenomenon of "young people."

I'm in the process of finishing an evidence-based book on mental illness; part science, part memoir. Please add your name to the mailing list and check back here for information on how to get free chapters. Thanks so much.