Long-term outcomes in schizophrenia - can some people do without meds?

There's another study by Martin Harrow which has been published online by the Archives of General Psychiatry:

Harrow, M., Jobea, T. H. & Faulla, R. N. (2012) Do all schizophrenia patients need antipsychotic treatment continuously throughout their lifetime? A 20-year longitudinal study [In Press: doi:10.1017/S0033291712000220]. Psychological Medicine.


It will undoubtedly get a lot of attention because of some of the inferences that are being made. Essentially, it's a longer-term follow-up from a previous study:

Harrow, M. & Jobe, T. H. (2007) Factors involved in outcome and recovery in schizophrenia patients not on antipsychotic medications: a 15-year multifollow-up study. Journal of Nervous and Mental Disease, 195, 406-414.

It's being implied (here, for example) that the drugs might account for some of the differences in outcome between those who took antipsychotic drugs for many years and those who didn't. It's important to acknowledge that antipsychotic drugs may have adverse effects on outcome - what's important is that Martin Harrow's studies don't confirm this.

The 2012 study reports 20-year follow-ups of a cohort of patients that consisted of 139 who were diagnosed early in their illnesses. The diagnoses were: schizophrenia (N=61); schizoaffective disorder (N=9); and psychotic mood disorders (bipolar, N=38; unipolar, N=31). All patients were diagnosed according to DSM-III.

Patients have been followed-up at: 2, 4.5, 7.5, 10, 15 and 20 years after first hospitalisation. It is worth acknowledging that this kind of extensive follow-up is hard to do and rarely-done. In psychiatry, a one-year follow-up study is long-term. Harrow and Jobe (2012) have followed up 59 (84.3%) of the 70 patients with schizophrenia, and this group forms the basis of the most recent paper.

Some headline outcomes include:

• A greater proportion of patients who weren't on medication were in 'recovery' ("no positive or negative symptoms, and no rehospitalizations during the follow-up year") at each time point. See Figure 1, below.

• Those on antipsychotics had higher levels of anxiety at each time point. See Figure 2, below.

Of course, it's difficult to know whether there is a causal relationship. People on opioid painkillers are probably more likely to report pain than those who aren't, but we wouldn't necessarily suggest that the painkillers are the cause of the pain. We might reason that those with pain are more likely to need painkillers.

It is certainly possible that Martin Harrow is simply observing the same phenomenon - that those who have a better prognosis, and who have fewer symptoms over the years are least likely to be using antipsychotic medications. Indeed, in their 2007 paper they commented that: "The results suggest that the subgroup of schizophrenia patients not on medications was different in terms of being a self-selected group having better earlier prognostic and developmental potential." And in the 2012 paper they conclude that: "SZ patients not on antipsychotics for prolonged periods are a self-selected group with better internal resources associated with greater resiliency. They have better prognostic factors, better pre-morbid developmental achievements, less vulnerability to anxiety, better neurocognitive skills, less vulnerability to psychosis and experience more periods of recovery."

So, this is less about whether antipsychotics cause a worse outcome (since the study can't determine this), and more about the different paths that groups of patients take when they develop a schizophrenic illness.

I don't think that Martin Harrow is necessarily suggesting that the drugs influence outcome  per se, despite the fact that this is what is likely to be assumed by many readers.For example, the following are some comments from the Mad in America blog:

• "...those 'who were not on antipsychotic medications were significantly less psychotic than those on antipsychotics.'"

Again, we shouldn't be surprised. All this tells us that if you don't have psychotic symptoms, you probably don't need antipsychotic drugs. It doesn't mean that the drugs cause the symptoms. People who take inhalers for asthma are likely to have less good airways function, but it doesn't mean that inhalers reduce people's peak flow. The treatment with the drug is simply reflecting the need for ongoing treatment.

•  "This dramatic difference in anxiety symptoms remained throughout the 15 years, with more than half of those on antipsychotics still suffering from high anxiety at the end of 20 years."

Indeed, the differences in anxiety levels are notable (see Figure 2 above). However, it's hard to know what this is showing. Would anxiety levels (if due to drugs) take more than 2 years to develop? Possibly, but unlikely. Remember that differences between groups aren't that marked (in terms of recovery) at two years (see Figure 1 above), so all we can perhaps conclude is that the two different courses haven't separated out. When people start developing less favourable rates of recovery, their anxiety symptoms are higher than those patients who have greater recovery. It shouldn't be that surprising that for those with persistent symptoms, one of the symptoms is anxiety since this symptom is extremely common in most mental disorders.

• "At three of the six follow-ups, those off antipsychotics showed significantly better cognitive functioning, and in the other three follow-ups, there was a general trend favoring those off antipsychotics."

This isn't necessarily the case, and there are other ways of interpreting the data. The cognition data are as follows (Figure 3, below).

The data show that cognitive performance is relatively stable for those on meds, whilst it is highly variable for those not on meds. The differences between the groups aren't statistically significant between 2-10 years, and at 20-year follow-up. It's worth bearing in mind that one-in-six patients weren't assessed at 20-year follow-up, and it's possible that different patients are being tested at different time points; making reasoning about associations shaky.

What the Harrow long-term data do suggest is that some patients who have a diagnosis of psychotic illness don't necessarily need long-term antipsychotic drugs in order to have favourable outcomes, and many patients who don't take drugs do better than many patients who do. However, what the Harrow studies don't tell us is how to determine if a patient with newly-diagnosed schizophrenia will be in the good-outcome/ few drugs group. There are clues (discussed in the 2007 study cited above) regarding pre-morbid functioning and adjustment that are associated with a better prognosis but questions remain whether this can be translated into recommendations and confidence for specific patients.