Before the advent of antipsychotic medication the treatments available to the psychiatrist were, with the exception of ECT, ineffective.  Things changed in 1950 when chlorpromazine was first synthesised; now for the first time people working with the mentally ill had a way of improving the previously pretty dismal outcome for sufferers of schizophrenia.  As discussed by Trevor Turner, this also improved the respectability of the psychiatric profession and provided the basis of an aetiological theory for psychotic illness. 

Other medications followed in Chlorpromazine’s wake.  These have become known as the ‘typical‘ antipsychotics and examples are Haloperidol and fluphenazine.  Although good at reducing some of the symptoms of schizophrenia, they also produced some horrid side effects, most notably Parkinsonian symptoms and another movement disorder called tardive dyskinesia.  

In 1958 Clozapine was developed.  This was the first ‘atypical’ antipsychotic.  Its difference was that it wasn’t nearly such a good blocker of D2 receptors, but had more activity at many other receptors including dopamine D4.  It causes no tardive dyskinesia and leads to some improvement in schizophrenic negative symptoms.  Other atypical drugs have followed, these include Olanzapine, Quetiapine and Risperidone.  They too are less potent D2 receptor blockers, and are less likely to cause tardive dyskinesia.  These newer drugs are currently the most widely used, although there is research that they are no better than the older and cheaper drugs at improving patient outcome. 

Clozapine is the ‘psychiatric domestos’ of the title. It’s what psychiatrists use when all the other treatments of psychosis have failed and when it works it’s pretty impressive.  As a medication it’s not without a chequered past and during the 1970s it was withdrawn because of its association with neutropaenia (3% of patients) and agranulocytosis (0.8%); however it was reintroduced following a study which proved it was more effective than other antipsychotics.  Although it does not cause movement disorders, it does have a lot of other side effects, most notably hypersalavation, sedation and diabetes. Why it works more effectively than other drugs is unknown; although its action at D2 receptors is reduced, this still appears important.  No one has ever synthesised an antipsychotic with no D2 activity.  

So, these days, Clozapine is given to our most treatment resistant schizophrenic patients.  It’s an expensive operation.  Each patient requires strict monitoring including regular blood tests and there are dedicated ‘Clozapine clinics’.  I hope that within my lifetime we’ll look upon it as a hopelessly antiquated way to treat our most difficult patients, but for now its the best we’ve got in an area where the search for new medication is frustratingly slow.  

It’s a bad time to be an SSRI antidepressant.

Strike one:

In January a paper in the NEJM found that the evidence base for the use of these drugs was incomplete, with a large publication bias towards positive results.  When negative results had been published, it was in such a way as to give these results a positive skew.  This publication bias in itself does not mean that a drug is ineffective, but hardly instills confidence.  There have been rumblings about this sort of thing going on for a long time….

Strike two:

A paper published today in the Public Library of Science Medicine Journal entitled Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration collected (via the freedom of information act) what it believes to be all the trial data available before their licence was granted (published and unpublished, positive and negative) on Fluoxetine, Paroxetine, Venlafaxine and Nefazodone, and found via meta-analysis their effects for mild and moderate depression to have no clinical improvement over placebo. 

This raises a number of concerns for psychiatrists and the population at large, several million of whom were taking these medications at the last count.

• Already not especially convincing, where does this leave the monoamine theory of depression?
• Have pharmaceutical companies deliberately mislead the doctors and patients as to the effectiveness of their product, thereby costing health providers billions of pounds and subjecting millions to ineffective medication and unnecessary side effects?  If so, shouldn’t we take them to court or something?
• What should we tell our patients?  There are plenty of people out there on the above medications for mild/moderate symptoms of depression.  See end of piece for a quick summary of how depression is categorized.  Doctors who prescribe antidepressants in these circumstances will be aware that it’s not the best treatment, but wouldn’t wish to give somethings that really doesn’t work at all.  If these antidepressants were working because of a placebo effect then, with all this publicity, they won’t be working now.
• What are we going to do instead?  NICE already recommends that counselling/therapy is the most appropriate intervention in mild/moderate depression.  However waiting lists are very long and many people crave a quick fix to their problems, which in any case are more ingrained than that which is amenable to a course of cognitive behavioural therapy.

Classification of depression

Depression as an illness is somethings that’s talked about a lot these days.  The first thing to say is that the difference between ‘depression’ as an illness and simply feeling ‘gloomy’ is not qualitiative but quantitative.  There is also no test for depression, but rather a line in the sand that when (methaphroically) overstepped people say that you are depressed.  The diagnosis of depression is made on clinical grounds rather than via a test.  This is not unusual in medicine, epilepsy for instance is diagnosed in the same way.

When we as psychiatrists, (but also as lay people, but in a less formalised way) say that someone is depressed, what me mean is that they are displaying a number of symptoms that suggest to us that their main problem is of low mood.  In order to make diagnoses more consistent and also to aid in professional communication psychiatrists use diagnositic guidelines for their diagnoses.  In America these guidelines are called the Diagnostic and Statistical Manual edition IV and in Europe we mostly use the International Classification of Diseases edition 10. 

(I’m almost there.)

Although mood and hence depression exists on a dimension, i.e. there is a continum from ‘not depressed’ to ‘very depressed indeed’ with no breaks in between, we choose to draw further lines in the sand and make categorical diagnoses - this is where the mild/moderate/severe depression diagnoses come from. 

So, when the above study talks of ‘mild depression’ it’s saying that a person meets the criteria for either the DSM-IV or ICD-10 criteria for depression.  The ICD-10 criteria are:

F32.0 Mild Depressive Episode: Diagnostic Guidelines
Depressed mood, loss of interest and enjoyment, and increased fatiguability are usually regarded as the most typical symptoms of depression, and at least two of these, plus at least two of the other symptoms described above should usually be present for a definite diagnosis. None of the symptoms should be present to an intense degree. Minimum duration of the whole episode is about 2 weeks. An individual with a mild depressive episode is usually distressed by the symptoms and has some difficulty in continuing with ordinary work and social activities, but will probably not cease to function completely.

If you’re interested in classification of depression then try this site

Roundup

Bad Science on SSRIs and criticism of media response to PLOS paper

Guardian articles on PloS paper: Ann Robinson - If the drugs don’t work; Allegra Stratton - A bitter pill; Sarah Boseley Prozac, used by 40m people does not work, say scientists; Mark Lawson Something for Nothing

In the 1950s and 1960s a pharmacological revolution produced an array of drugs for use in disorders such as schizophrenia, depression and anxiety which enabled psychiatry to move closer to the paradigm of physical medicine of administering specific cures for specific conditions. Consider the following statistics

In the UK the use of antidepressants increased by 234% in the 10 years up to 2002 (1).

In the USA 11% of women and 5% of men now take antidepressants. (2)

What can be causing this explosion in the demand for prescription antidepressants? It cannot be possible that in ten years the number of people suffering from depression in the UK has more than doubled.

Here are some of the possibilities:

In recent years we have been encouraged to view more and more problems that were previously considered to be normal and manageable parts of the human condition as mental diseases that require treatment.

The boundaries of well known disorders have been broadened. Psychiatric diagnoses are very changeable and what counts as a disorder is highly dependent upon prevalent social norms and beliefs. We are now inclined to medically characterise the ‘problems of living’.

Lesser known disorders such as panic disorder and social phobia have been publicised. These disorders can have a substantial overlap with normal experience. When this is the case the condition is then expandable, which allows the drug companies may claim that they abhor the inappropriate over-prescribing of their drugs safe in the knowledge that this will almost certainly occur anyway.

Drug treatment has started to colonise areas where it was previously thought to be unhelpful such as substance misuse and personality disorder.

Depression as a diagnosis has been promoted by drug companies, especially after the advent of Selective Serotonin Reuptake Inhibitors (It has been suggested that pharmaceutical companies turned their attention to antidepressants after the collapse of the market for benzodiazepines following the discovery of their addictive potential (3)

It is more acceptable to admit to being depressed

Antidepressants have become household names and books about them have become best sellers.

There are social advantages by being depressed. A ‘depressed’ person can be seen as less responsible for their behaviour and can lay claim to the sympathies of professionals, the resources of the welfare state and the language of victimhood.

Although we are living longer, our modern lives are becoming increasingly uncertain. The comforts of the welfare state are less, our working hours increased, job security decreased and pension schemes uncertain. We are actively encouraged by the media to be in a semi-permanent state of mild dissatisfaction in order to fuel consumer spending and are constantly fed a diet of soundbites fortelling imminent doom.

Why is this important?

Medications cost a lot of money. This money might be better spent elsewhere and could go towards other non drug based therapies

A society which has been convinced that it is ill is less likely to look for other solutions to tackling misery for example that their social conditions are caused by wanting Government policy and will be unable to mount an effective challenge.

Psychiatric illness is poorly understood and the ‘biological hypothesis’ of this sort of disease is unproven.

We disempower people by informing people that their only form of relief of their mental distress is via medication.
The idea that problems that were previously considered a manageable part of human existence are now only to be addressed with the help of professionals is likely to reduce personal coping stratgies (4) and reduce our self confidence’

Medications have side effects, some of these can be very serious and there have been allegations that pharmaceutical companies have sought to play down the harmful effects of their products. Many psychoactive medications have a deleterious effect on sexual function, something about which patients are seldom asked.

Ben Goldacre has made available an interesting podcast entitled ‘More than molecules – how pill pushers and the media medicalise social problems’ - in which he argues that the media are locked in a ‘Miracle cure/sinister hidden scare’ model and that pharmaceutical companies seek to sell us preparations which they invite us to believe can cure complex social problems.

1 National Institute for Clinical Excellence (2004) The Treatment of Depression in Primary and Secondary Care. London: NICE
2 Stagnitti, M. (2005) Antidepressant Use in the US Civilian Non-Insitutionalised Population, 2002. Statistical Brief #77. : Rockville, MD: Medical Expenditure Panel, Agency for Healthcare Research and Quality.text
3 Healy, D. (1999) The three faces of antidepressants. Journal of Nervous and Mental Disease, 187, 174-180.
4 Moncrief, J. (2003) Is Psychiatry for Sale? Maudsley Discussion Paper