Monday, 13 September 2010

Shotgun Psychiatry

There's a paradox at the heart of modern psychiatry, according to an important new paper by Dr Charles E. Dean, Psychopharmacology: A house divided.

It's a long and slightly rambling article, but Dean's central point is pretty simple. The medical/biological model of psychiatry assumes that there are such things as psychiatric diseases. Something biological goes wrong, presumably in the brain, and this causes certain symptoms. Different pathologies cause different symptoms - in other words, there is specificity in the relationship between brain dysfunction and mental illness.

Psychiatric diagnosis rests on this assumption. If and only if we can use a given patient's symptoms to infer what kind of underlying illness they have (schizophrenia, bipolar disorder, depression), diagnosis makes sense. This is why we have DSM-IV which consists of a long list of disorders, and the symptoms they cause. Soon we'll have DSM-V.

The medical model has been criticized and defended at great length, but Dean doesn't do either. He simply notes that modern psychiatry has in practice mostly abandoned the medical model, and the irony is, it's done this because of medicines.

If there are distinct psychiatric disorders, there ought to be drugs that treat them specifically. So if depression is a brain disease, say, and schizophrenia is another, there ought to be drugs that only work on depression, and have no effect on schizophrenia (or even make it worse.) And vice versa.

But, increasingly, psychiatric drugs are being prescribed for multiple different disorders. Antidepressants are used in depression, but also all kinds of anxiety disorders (panic, social anxiety, general anxiety), obsessive-compulsive disorder, PTSD, and more. Antipsychotics are also used in mania and hypomania, in kids with behaviour problems, and increasingly in depression, leading some to complain that the term "antipsychotics" is misleading. And so on.

So, Dean argues, in clinical practice, psychiatrists don't respect the medical model - yet that model is their theoretical justification for using psychiatric drugs in the first place.

He looks in detail at one particularly curious case: the use of atypical antipsychotics in depression. Atypicals, like quetiapine (Seroquel) and olanzapine (Zyprexa), were originally developed to treat schizophrenia and other psychotic states. They are reasonably effective, though most of them are no more so than older "typical" antipsychotics.

Recently, atypicals have become very popular for other indications, most of all mood disorders: mania and depression. Their use in mania is perhaps not so surprising, because severe mania has much in common with psychosis. Their use in depression, however, throws up many paradoxes (above and beyond how one drug could treat both mania and its exact opposite, depression.)

Antipsychotics block dopamine D2 receptors. Psychosis is generally considered to be a disorder of "too much dopamine", so that makes sense. The dopamine hypothesis of psychosis and antipsychotic action is 50 years old, and still the best explanation going.

But depression is widely considered to involve too little dopamine, and there is lots of evidence that almost all antidepressants (indirectly) increase dopamine release. Wouldn't that mean that antidepressants could cause psychosis (they don't?). And why, Dean asks, would atypicals, that block dopamine, help treat depression?

Maybe it's because they also act on other systems? On top of being D2 antagonists, atypicals are also serotonin 5HT2A/C receptor blockers. Long-term use of antidepressants reduces 5HT2 levels, and some antidepressants are also 5HT2 antagonists, so this fits. However, it creates a paradox for the many people who believe that 5HT2 antagonism is important for the antipsychotic effect of atypicals as well - if that were true, antidepressants should be antipsychotics as well (they're not.) And so on.

There may be perfectly sensible answers. Maybe atypicals treat depression by some mechanism that we don't understand yet, a mechanism which is not inconsistent with their also treating psychosis. The point is that there are many such questions standing in need of answers, yet psychopharmacologists almost never address them. Dean concludes:
it seems increasingly obvious that clinicians are actually operating from a dimensional paradigm, and not from the classic paradigm based on specificity of disease or drug... the disjunction between those paradigms and our approach to treatment needs to be recognized and investigated... Bench scientists need to be more familiar with current clinical studies, and stop using outmoded clinical research as a basis for drawing conclusions about the relevance of neurochemical processes to drug efficacy. Bench and clinical scientists need to fully address the question of whether the molecular/cellular/anatomical findings, even if interesting and novel, have anything to do with clinical outcome.
ResearchBlogging.orgDean CE (2010). Psychopharmacology: A house divided. Progress in neuro-psychopharmacology & biological psychiatry PMID: 20828593

19 comments:

Anonymous said...

Dopamine "is the devil", it's well known.
Actually Rifat blew himself off in 2002 but it wasn't the fault of dopamine...

Art said...

And maybe we can show pretty much anything works for depression assuming it's effects are clearly noticeable (not blind) and you happen to be lucky/try hard enough. There is a reason many pharma companies have abandoned antidepressant development, as they have no way to predict success in phase III trials.

See this NIMH initiative for a potential way out of this dead-end DSM/subjective scales street.

Dee said...

I know only this: Seroquel worked for about a year on my young son, who is bipolar and has behavioral issues. After that he had pseudo-seizural collapses into sleep and hallucinations. We quickly weaned him off of it and he became so disturbed that he broke my arm in an outburst. Now he is stable on other medication that I'm still unhappy with, but at least he knows which end is up and what is real.

Being a chronic depressive myself and having been through most types of the antidepressive medications, I wouldn't go to the atypicals with a ten foot pole. I hate that we have to use them to help my son, who seems happy and well on them. I dread the reckoning later in life.

moodspectrumindigo said...

It makes sense that if a disorder is unique then it should respond to a drug that isn't used for another type of disorder,however there are different medical conditions that respond to the same drug and yet they are viewed as being quite different.

An example might be the fact that antiseizure drugs are used for both epilepsy and migraines.The pathology of migraines has not been established, much like depression, however it is still viewed as being distinct form epilepsy.

It seems like if one questions the validity of mental disorders then the validity of other illnesses with no known pathology needs to be addressed as well.

Depression could appear to respond to a a wide variety of drugs because it hasn't been defined well enough.It is composed of an somewhat odd conglomeration of symptoms- agitation in some people and lack of interest in others.

Kelly said...

I would just point out that depression and mania are not actually opposites - there are mixed states in which people have an 'activated' depression that has many similarities to mania. The notion of behavioural opposites or ups and downs is outdated and simplistic.

Otherwise - I love your blog!!

Mike said...

The antidepressant question is so obvious and has been answered several times over: antidepressants are nothing more than active placebos. Patients perceive they are being treated because they experience side effects and they get better because of it - this accounts for the differences in treatment outcomes between drug and control groups in pharmaceutical trials.

There is no chemical imbalance. You can take pretty much any drug, tell a patient it's an antidepressant and get the same level of clinical response. That is why a serotonin reuptake enhancer is as effective as an SSRI, that is why antipsychotics, anti-anxiety, and drugs designed for hypertension can effectively serve as antidepressants.

Irving Kirsch sums it up nicely in this fantastic book: http://www.amazon.com/Emperors-New-Drugs-Exploding-Antidepressant/dp/1847920837

Anonymous said...

And maybe the curative factors for psychiatric "disorders" or "diseases" or "syndromes" are non-specific. Which would really be a hoot and call into question the entire scientific basis of psychiatry.

Neuroskeptic said...

moodspectrumindigo: That's a good point.

In a similar way, SSRIs are used to treat psychiatric disorders, but they also suppress appetite (presumably via actions in the hypothalmus) and they delay ejaculation (I believe is at the level of the spinal cord).

So though they are very selective pharmacologically, they have several quite different effects, because they hit different brain regions.

So yes, the fact that SSRIs are used to treat depression, anxiety and OCD doesn't prove that they're not distinct diseases.

However, given that there's also loads of clinical overlap and comorbidity, it's not implausible.

Anonymous said...

Delay ejaculation? Like prevent premature ejaks? Really? Gosh that's a hot point.

Neuroskeptic said...

Yeah, they're used for that. In fact Eli Lilly recently, er, released a new short-acting SSRI specifically for premature ejaculation.

Anonymous said...

I don't understand the logic behind this statement: "If there are distinct psychiatric disorders, there ought to be drugs that treat them specifically."

This is quite counter-intuitive, unless perhaps you replace "specifically" to "differentially." But it seems more likely that there may be psychiatric illnesses for which there will never be a useful drug treatment (at least as we understand drugs today).

Anonymous said...

Another possibilty is that what we call "depression" is actually many diseases and our current technology just can't differentiate between them. I seem to remember that atypical depression was thought to be an environmental form of depression while the melancholic form was more biological and I think I saw a couple of papers that found a history of abuse was more common in people with atypical vs melancholic depression.
My field is genetics, and I suspect that this also has something to do with the difficulty in identifying polymorophisms/mutations raising susceptibility to depression aside from that 5-htt polymorphism. (It seems as if you usually need two first-degree relatives to be depressed to be in these genetic studies.) I would expect different polymorphisms in a family with very severe symptoms, age of onset 13-30 with an autosomal dominant, highly penetrant even in the absence of trauma inheritance pattern than in a family where the illness is less severe and the age of onset is 25-40 with an autosomal, moderately penetrant depending on trauma inheritance pattern. Especially if symptoms tend to be consistent within the family but different between the families. You might have mutations in different genes and possibly different pathways leading to disease.

Anonymous said...

Maybe the drugs don't work on all those illnesses, considering most people on the medication still show signs of their illness. So while it may treat more than one thing, doesn't mean it should be assigned to all the diseases.

A knife can cut many things, from meat to wood. But does that mean the knife should be used for cutting ? No, a better choice would be an axe or a saw. A knife can cut paper, but you might notice that while it might get through that paper, it doesn't make the knife the right tool because it cannot effectively work in all aspects scissors can.

So I am not going to hand you a knife cause it can cut meat and paper. I'm going to hand you a knife for the meat and scissors for the paper: specific tools for specific tasks.

Anonymous said...

Perhaps the logic is faulty. By insisting unilaterally these experiences are diseases, it must then be assumed they all can be treated by drugs. Is the treatment defining the condition?

Neuroskeptic said...

Anonymous: I like the knife analogy: I think that sums it up pretty well.

Velvet Elvis said...

I've always considered the most likely case to be that since AAPs take such a shotgun approach, affecting so many receptor sites, they have the greatest chance of being effective for the greatest number of conditions.

The point of failure that forces this is in the DSM diagnostic categories which fail to adequately describe psychiatric conditions as they actually exists so only drugs that treat everything can actually get through trials. If we had a way to do finer grained diagnostic assessments, drugs could be approved that treat more specific conditions. Until neuroimaging or a better DSM allows for a better diagnostic process, we'll be stuck with these shotgun remidies

The Athomium said...

This is always SO difficult to discuss as there are those who's acceptance of diagnoses has caused a lengthy period of associated symptoms. Steeped in a solid 'Person Centred' model of psychiatry (nursing UK), I am well versed in individual's resentment at having a diagnosis questioned. In many instances, the psychiatrist will treat because they are expected to rather than wait and allow the human contact to do it's stuff...

Psychiatrist said...

The Psychiatrist goes to medical school after the undergraduate studies, and is required to perform a period of residency in psychiatry in a hospital. It is during the residency that the Psychiatrist usually tends toward one area of specialty or the other.

Lane Archie said...

another thing to know is, if you pay for treatment yourself you can ask the therapist to NOT make or record a diagnosis, thereby getting help if you want it but avoiding the lifelong label of being "bipolar" or
"schizophrenic" or whatever