What good are antidepressants?

by Ruth Laugesen / 22 October, 2011
For mild and moderate depression, antidepressants may not be the miracle pills their advocates claim.
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Wellington suburban GP Ken Greer pricks up his ears whenever a patient complains of problems sleeping. It’s Greer’s cue to start probing more deeply, “and soon it all comes out”. Often the problem is depression. Like other GPs, Greer has been prescribing antidepressants for an increasing number of patients over the past decade, and he finds he gets good results.

“To me, people who are not sleeping, who are feeling down and weeping, have no energy, and for whom everything’s an effort, they are very significantly depressed,” says Greer. “The response rate among that group of people is really high. Most of them get better – talking to them, counselling them and supporting them, at the same time as giving them medication.” Some patients find it’s not only their depression that clears, but also all their social anxiety. These patients are reluctant to stop taking antidepressants, because they like their new, confident selves.

But there is another group, in Greer’s experience, who don’t respond as well to medication. He calls these people “life’s unfortunates”, often individuals with fragile, difficult personalities, who clash with those around them, who get into unhealthy relationships and whose lives become a series of dramas.

Twenty years after Prozac and a new generation of SSRI (selective serotonin re-uptake inhibitors) antidepressants became available in New Zealand, antidepressant use is still climbing steeply. Prescribing has nearly quadrupled since 1993, and grown nearly 40% in the past five years. Pharmac estimates some 400,000 New Zealanders, or about 10% of the population, are on antidepressants. Research suggests 21% of New Zealanders had a diagnosable mental disorder in the previous year (including addiction), of which 5% were classified as serious.

Thanks to public campaigns on depression, such as John Kirwan’s, awareness of the condition is at a new high. But a growing body of international research has raised questions over whether antidepressants work as well as we think they do. For severe depression, medication is still the standard treatment, accompanied by psychological therapy. But at the mild and moderate end, which makes up the majority of cases, doctors aren’t exactly sure who to medicate, whether the pills are the cause of any improvement and when to stop. Adding to the issue’s complexity, individual responses to antidepressants can differ wildly.

To treat or not

The question at the mild to moderate end is whether to treat at all, says University of Otago head of primary health care and general practice Professor Tony Dowell. The median length of time for depression is around three months, and many cases are resolved spontaneously. Often the onset is linked to a traumatic event, such as a job loss or marriage break-up.

“We should recognise the fact that people can be pretty resilient, and that we should allow for that and support that instead of rushing to a label of depression or anxiety. The key question would be firstly: is doing something better than doing nothing? We don’t have the naivety of 10 to 15 years ago, when people thought that antidepressant drugs were the answer to everything. It is clear that both talking therapies and pharmacological therapy in some instances are better than placebo. How much more effective they are than placebo is still under question, and rightly so. Social networks, good therapeutic relationships, counselling and positive psychology are what we should be focusing on for those with mild to moderate disorders.”

And he says knowledge is patchy about when to stop antidepressants. Many patients are on long-term treatment from their GPs to prevent recurrence, but little is known about how many need it long term and how many could safely come off it. Looming behind all this is greater cynicism towards drug companies, after the revelation that ghostwriters have been used to massage scientific papers, and that only the most positive trials data become public.

“I think we’re in a phase of disillusionment at the moment,” says Professor Pete Ellis, head of psychological medicine at the University of Otago. “Drug companies are in the business to sell drugs and to make profits, and I think probably in the past people have been a little naive about what that means.” Ellis says he has become “a little more reluctant” to prescribe antidepressants. “Whereas maybe 10 years ago I would usually have seen an antidepressant as part of the treatment I might be recommending, now it’s ‘often, but not always’.” Are patients responding better to this treatment? “I don’t think the results are any worse.”

Trials and errors

Several studies have helped spoil the rosy glow around Prozac and other SSRIs, one by an expert on the placebo effect, the University of Hull’s Irving Kirsch. He and his colleagues gained access to all drug trials submitted to the US Food and Drug Administration in the late 1980s and 1990s for the six most popular new SSRIs. These included unpublished drug trials. As outlined in his 2009 book, The Emperor’s New Drugs: Exploding the Antidepressant Myth, Kirsch found overall placebos were 82% as effective as the drugs were, when measured by the Hamilton Depression Scale, which is used to score symptoms of depression. The average difference between drug and placebo was 1.8 points on the depression scale, which is a small difference in clinical terms. The drugs were particularly unimpressive in the treatment of mild and moderate depression.

At about the same time, another research team in Oregon revealed how misleading the results of published drug trials can be. Comparing the published and unpublished trials for 12 antidepressant agents, they found that for published trials, 94% were positive, while in unpublished trials, only 51% were positive. Across all the trials, the drugs were between 11% and 69% better than placebo, with an average of 32%.

The findings have ignited intense scientific debate, and focused attention on the power of the placebo effect, thought to be bound up in the positive effects of a doctor giving a patient attention and treatment. A Swedish research team hit back with a 2008 paper that showed antidepressants were effective at all levels of depression, not just severe. British psychopharmacologist David Nutt has also challenged Kirsch’s findings, saying his overall results were skewed by the inclusion of one drug that has since been withdrawn for its ineffectiveness. The suggestion that antidepressants should only be used for severe cases “reintroduces a stigma about depression that we have fought hard to decrease”, says Nutt.

Who is right? The big picture, says Carl Burgess, professor of clinical pharmacology at the University of Otago, is “that although the antidepressants are better than placebo, they’re not nearly so good as you thought they were. Maybe some patients aren’t going to do as well as you think they are.” Burgess isn’t that worried by the finding that antidepressants are only 30% better than placebo – that’s similar to many drugs. The problem is that antidepressants also have serious drawbacks, and once a patient is put on them, it can be a long time before they come off. “Antidepressants are not sweeties, they’re actually drugs that have the potential to be very harmful in their own right.”

Although they are benign compared with the previous generation of anti-depressants, “they are not without risks”. The SSRIs and SNRIs can have cardiac and metabolic effects, can cause general weakness, sexual dysfunction and sleep problems, and of course are mind altering. In children there is evidence of suicide risk. One side effect people most dislike is a feeling of being wrapped in cotton wool, although not everyone experiences this.

Sexual dysfunction is common, and can wreak havoc on self-esteem and relationships. Studies estimate that anywhere between 2% and 70% of those taking SSRIs develop trouble with sexual performance. In the elderly, it has recently been discovered, SSRIs can lead to low salt levels in the blood, with potentially life-threatening results, leading to confusion, hallucinations and sometimes coma. As a general physician at Wellington Hospital, Burgess sees patients with a wide variety of complaints. Those on anti-depressants have often been put on them open-endedly. “They say, ‘When I stop my antidepressants then I find I can’t cope any more.’ In reality they have become addicted, not physically, but psychologically. I feel those sorts of people would benefit a lot from counselling and people talking to them.”

One reason antidepressants remain relatively blunt instruments is that it is far from clear what chemical mechanisms in the brain are involved in depression and to what extent these may vary in different people. For many years the leading hypothesis has been that depression is caused by a “chemical imbalance” in the brain, perhaps involving two chemical messengers or neurotransmitters called noradrenaline and serotonin

But the theory remains unproven, as it arose mainly from studies on animal brains rather than any evidence in people. The first two classes of antidepressants that appeared in the 1950s, tricyclics and monoamine oxidase inhibitors (MAOIs), were found to promote the availability of serotonin and noradrenaline, leading to the idea that a deficiency of the neurotransmitters might be the cause of depression. But evidence for this is scant, and just because a drug produces a measurable biological effect doesn’t mean that property is relevant to the disease the drug may treat. As some commentators have said, that is like saying because aspirin cures fever, a lack of aspirin in the body must be the cause of fever.

John Kirwin, photo Steven McNicholl/NZH


Beginning in 1989, the new SSRIs became available, targeting just the availability of serotonin in the brain. Such “clean” pharmacology is still associated with an impressive variety of potential clinical effects, both good and ill. A decade later, venlafaxine became available, and because it targets both serotonin and noradrenaline, its use in some ways reflects a return to the messier pharmacology of the old tricyclics. Venlafaxine is the first SNRI, a serotonin-norepinephrine reuptake inhibitor. Drug development for antidepressants is still a hit and miss affair, says Burgess. “What you’ve got is people messing about with the receptors.”

In New Zealand the big four antidepressants used are the SSRIs fluoxetine (Prozac), paraxetine and citalopram, along with the older tricylic amitriptyline. Another tricyclic, nortriptyline, is the next most popular, followed by venlafaxine, an SNRI. Not all of the drugs are used just to treat depression – tricyclics are also used at low dose for chronic pain or sleeplessness. Despite the soaring use of antidepressants in New Zealand, Pharmac’s hard-nosed bargaining has meant that, at $24 million last year, the cost is less than a decade earlier.

The rise of SSRIs has been accompanied by a significant decline in suicides, according to a Ministry of Health study that looked at the 1996-2005 period. But over the same time, hospitalisations for intentional self-harm “significantly increased”, the report said. Prescribing of nortriptyline, paroxetine and fluoxetine was associated with a greater likelihood of self-harm.

Chemical romance

The idea that depression is caused by a chemical imbalance in the brain, while still unproven, has become part of the popular lore about depression. And the thinking goes that if the problem is chemical, then the cure must be too. In fact that will differ from person to person, as depression is triggered by a complex mix of social, environmental, genetic and chemical factors. As we learn more about brain chemistry, says Tony Dowell, we will probably find one group of patients prone to depressive symptoms even when they’re not in a stressful situation. These people may well benefit from chemical rebalancing.

“But for most people I suspect it’s more complicated, it’s a bit of situational stuff, it’s a bit of underlying personality stuff, there’s a bit of underlying brain chemistry. You’re in that slightly messy position of saying it’s likely that either drugs or talking therapy will help those people a bit, and in time when the situation improves they probably could come off their treatment.”

University of Auckland associate professor of psychiatry David Menkes says one upside to the chemical imbalance idea is that it has been a positive force for enabling sufferers and their families to feel less stigmatised and less guilty, and perhaps being more likely to get help. But on the downside, people may feel disempowered by a medical diagnosis and chemical prescription. “People think, I’ve got this thing, I’ve got to see the doctor, I’ve got to get my prescription, I’ve got to take these pills, or I’m not going to get better because there’s this thing wrong with me.”

Apart from attending to problems that may be causing their depression, “many people are able to feel and cope better by doing things beneficial to mood, such as exercise, social activities and ‘pleasant event scheduling’. We often say, ‘Give yourself a treat, go out for a coffee, go see a film, ring up a friend you haven’t seen for a while.’ ”

Head of psychology at Otago Peter Ellis says although there is not yet a common view on what the biological mechanism is for depression, it is clear there is a change in brain metabolism or brain chemicals. “It’s still reasonable to say my brain isn’t working as well as it should be. I’ve got the John Kirwans, and these pills seem to work for me. And they’re correcting whatever isn’t working properly in the top storey.”

Wise counsel

Clinical psychologist and senior lecturer at the University of Auckland Kerry Gibson says she wouldn’t want to question anyone who needs antidepressants to get through their day, but her profession believes skilled counselling is more effective than drugs in tackling the underlying causes of depression. Psychotherapy allows people to make sense of what is causing their unhappiness and learn coping strategies for now and the future. The hitch is not only that counselling can be gruelling, but it costs $100 to $160 hour, and may take 10 to 20 sessions to get to the nub of things for someone with significant depression. Few can afford such personal attention, when a prescription costs $3 and the price of a GP visit.

Guidelines for general practitioners recommend that for mild depression, first-line treatment should not include drugs, and that for moderate depression, either SSRIs or a 10-12 week course of psychological therapy are equally effective. For severe depression, antidepressants and psychological intervention are recommended.

“Overall, the evidence suggests that psychological therapies and antidepressants are of comparable efficacy. Psychological therapies are better tolerated, and may have a more sustained effect,” say the guidelines, produced by a committee of experts for the New Zealand Guidelines Group. “Studies favouring exercise and guided self-help strategies have been conducted almost exclusively in volunteer populations but their findings may reasonably be applied to adults in primary care, particularly those with milder forms of depression.”

New annual Government funding of $25 million for primary mental healthcare means, for the first time, some counselling is available for free through GPs. In the 2010/11 year there were 25,000 extended consultations with GPs of up to 45 minutes; 57,500 interventions that included two or three sessions of counselling; and 21,000 “packages of care” that generally involved four to six sessions of therapy. The new funding is for patients with mild to moderate mental health or substance abuse problems in high need populations such as Maori, Pasifika and low-income populations.

Understanding unhappiness

Gibson says although she is pleased there is now greater awareness of depression, the flipside is that many people seem to feel “if you’re not happy then there’s something terribly wrong with you, rather than if you’re not happy it’s a normal reaction to life’s difficulties”. A label of depression “can put you in a box, saying it’s a medical problem that needs to get sorted, as opposed to recognising that this is something that you, with help, need to work on”. We have become distracted, says Gibson, by the idea of depression as a list of symptoms to be treated, such as sleeplessness, low mood and lack of energy.

“But if you ask any person what it is, the person has a state of feeling ‘I don’t feel good about myself, I don’t feel I’m worth anything, I don’t feel that my future holds anything meaningful for me’. The experience of depression is very much about those kinds of questions; that’s certainly part of what psychotherapy can address.” Dowell says no one knows exactly how many people are really benefiting from taking antidepressants. In part, it is a philosophical question.

“Underneath it is a deeper question for society, which is our expectations around happiness. My observation is that doctors just don’t prescribe willy-nilly. But you’ve got quite significant changes in society, where people are saying if this drug is working for me, I’m going to carry on with it. These are the lifestyle drugs, the happiness drugs. It’s very difficult to say we the health profession or we the government have decided you can have this for three months, and that’s it.”

"YOU REALLY HAVE A COMPLETE NUMBNESS"


Drugs caused blogger Cameron Slater to be callous and hurtful.

Cameron Slater, photo/David White


Just before Christmas last year, blogger Cameron Slater, known for his aggressive, attacking writing style, posted some unusually tender comments on his blog, Whaleoil. It was an apology to all those he had hurt. And it was a resolution he was going to change.

“I am going to treat people like I want to be treated. I will address the real reasons for my depression. I will learn to love myself again.”

Just a few months before, Slater had begun weaning himself off six years of antidepressants after deciding the drugs were making him sicker. He had been through a hellish struggle since major depression had first poleaxed him, leaving him unable to work. A succession of common antidepressants – Prozac, citalopram, venlafaxine, Zyban – didn’t help with the  depression, and made him behave  in a callous way to his loved ones.

“You really have a complete numbness in terms of interpersonal feelings, so I would say some of the most hurtful things to the people I cared the most about and they would react in the most appalling way, breaking down or crying, and you just don’t care. You just shrug your shoulders. That creates a callousness that just keeps building. I got fed up with not caring or feeling. I wouldn’t be surprised if some people suicide on these drugs because they want to feel something, anything.”

The antidepressants made him sweat  a lot, which made him smell, and caused sexual dysfunction, which made him feel worse about himself. “If they told blokes in the doctor’s room that if you take these then it’s going to seriously stop your sex life, men just wouldn’t want to take them.” In the past two years Slater also developed depersonalisation disorder, a frightening and difficult-to-treat condition in which sufferers feel disconnected from their own experience. Slater says he would watch his life unfolding as if he was sitting on his own shoulder, or watching a movie. “I feel that the drugs, and the experiences and side-effects of the drugs, caused the depersonalisation.”

The final drug the doctors tried Slater on, a maximum dose of venlafaxine, was a last resort. It made him constantly hot. Slater began weaning himself off  the medication with his doctor’s  agreement. Now he is drug-free and has a new regime: a 10km walk every day or a session at the gym; a Berocca every morning; and a vitamin B injection every three months. He has also realised that if he gets tired and run down, that can tip him into depression. He is getting some paid work again this year, after years on insurance payments and then a sickness benefit. The day the Listener rings, he rates his mood an eight or nine out of 10.

As for whether he is being any kinder on his blog, many of his targets might not think so. Whaleoil is still a particularly aggressive political blog. But Slater says he has toned down some of his most vicious personal vendettas and name-calling, such as against Labour MP Stuart Nash. What is it that has most helped? Seeing a psychologist. “I had shitloads of counselling over six years. I thought there were underlying reasons for my depression. I found that the most effective therapy. But you’ve got to find a counsellor who works well with you.” He thinks he initially became depressed because of profound physical and emotional exhaustion.

Exercise has also been critical. But surely if you are extremely depressed, it is impossible to drag yourself out of bed to exercise? Yes, he says, there were days he would get to the end of his driveway and be immobilised, unable to decide whether to go left or right. But once he eventually got going, he would start to feel better. “You have  got to get yourself out of bed and out walking or doing something, because the drugs aren’t going to do that for you. They’ll just leave you in a zombie state for three or four years or longer. And the longer you’re on those drugs, the harder it is to get off them.”

NO WORRIES


Patrick Smellie


Wellington business journalist Pattrick Smellie began taking antidepressants nine years ago, when struggling with a mid-life crisis full of distress, anxiety and overload. The counsellor he was consulting suggested he try medication. “For the first couple of weeks I thought nothing was going to happen. But I remember very distinctly one evening getting ready for bed, thinking, ‘Hang on, I’m not obsessing about problems at work tonight.’ Over a period of time I became aware I was much less anxious than I had been, and had probably been over my entire adult life. I don’t think that the depression was experienced so much as a mopeyness, but as a constant level of anxiety about everything.”

Smellie takes fluoxetine, originally marketed as Prozac, and has no plans to stop. “It took the edge off in a very helpful way. It made life a lot more enjoyable. For the last couple of years I thought maybe I should stop, but I can’t think why. The part of me that is very anxious I’m glad to be shot of it. Some friends tell me I should stop, which I find very irritating. It’s almost like they’re saying it’s a weakness and you need to move on. But I’m much happier than I used to be, so bugger that.” In terms of what might be the cause of his underlying anxiety, he knows many people who have had tougher lives than he has had. He thinks it is probably just part of his makeup. Smellie says he has noticed no impact on his physical or sexual health, and he hasn’t had the emotional numbing some suffer from.

“Some people say they don’t experience the highs and lows when they are on antidepressants, but that hasn’t been my experience. How people experience them seems to be quite a personal thing.” As well as having counselling, he has done personal development through the Landmark courses, which helped him realise he is in charge of the direction of his life. He is also on an exercise regime. Smellie says on the odd occasion  he misses a few doses, the old anxiety creeps back again in a few days. “I become more stressed, more easily angered, more easily upset by things, more easily knocked off balance, more inclined to ruminate on stuff. I think the medication has helped me not sweat the small stuff so much. My experience is broadly positive apart from the occasionally judgmental views of friends who say to stop.”

WE HAVE RECEIVED THE FOLLOWING LETTERS IN RESPONSE TO THIS STORY


Last week's article on antidepressants was fascinating. Your gentle readers may like to try a natural high that I have found amazingly effective. This is the green smoothie. Instead of your normal breakfast simply replace with a green smoothie and eat nothing else until lunchtime. While you may think this will not be enough to sustain you without getting hungry you will be surprised. The benefits occur almost immediately so there is no need to wait weeks to see how effective the green smoothie is. Although I was not depressed to start with I was having no sales in my Real Estate venture which is naturally depressing. Despite this I always felt on top of the world thanks to my breakfast green smoothie. I also found that I used to lose energy in the late afternoon and got extremely lethargic. This afternoon lethargy disappeared completely after I started on the smoothies. I also found that I need much less sleep - often waking at 4.00am rearing to go. The key to a green smoothie is raw green leafy vegetables whizzed up with fruit to make it palatable. The theory is that the plants absorb the sunlight and you are eating that goodness without first diluting it by cooking. A common smoothie I make has spinach leaves, an apple, banana, pear, kiwifruit, lemon and fruit juice. Or replace the spinach with silverbeet, celery, kale or bok choi. Add berries or ginger to spice up. Don't use the same green too often in a row and don't juice the smoothie or that will negate the effect. Enjoy that delicious green smoothie and say goodbye to depression.
Peter Clark
Nelson


Fluoxetine, paroxetine, citalopram, amitriptyline, nortriptyline – I’ve been prescribed them all, and lots more besides, for severe intractable clinical depression. Did they help? I doubt it. At one stage I was taking 13 prescription drugs – for the original illness as well as for the side effects from the medication. Counselling has been the only thing with long-term sustainable benefits. I commend the Government’s initiative to provide counselling through GPs, but it is much too little for someone with a serious mental illness. Although long-term counselling has always been seen as too expensive, it is also too expensive not to provide it. I spent two years of my life (over a decade) as an inpatient in mental hospitals. The $1000 a day, or whatever it costs to stay in hospital, could have bought a lot of counselling. While I was in hospital, I saw the same faces coming back again and again. The drugs alone cost a small fortune, never mind the hospitalisations. How much are 1.3 million antidepressant prescriptions costing our country? Drug companies fund research into mental health outcomes but seldom fund studies into the effectiveness of counselling alone. They also fund the publication of the medical journals that surprisingly seldom publish results of studies relating to the effectiveness of counselling. There is a lot of money to be made from antidepressants, because modern life is stressful for many people. My experience has shown mental health providers use drugs first, then hospitalisation, and if these don’t work, go for ECT. Because of the way they have been trained, the “medical model”, they do not see long-term counselling as a serious option for the severely depressed. After two decades on a huge range of drugs, I have now gone three years drug-free and have had no hospital admissions during that time. Although I am not able to work, I am able to look after myself and be relatively independent. I believe good psychotherapy is worth its weight in gold. It is time at least half of the money being spent on antidepressants was used to fund psychotherapy, and let’s see what the results tell us about its effectiveness.
(Name and address supplied)
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