Epistemic Status: pretty rough, a first pass

A friend of mine recounted a pretty terrifying description of his experience being on antipsychotics for years as a child:

Antipsychotics can make you dumber. So can a lot of other medications. But with antipsychotics it isn’t the normal sort of drug-induced dumbness – feeling tired, or distracted, or mentally sluggish, say. It’s more qualitative than that. It’s like your capacity for abstract thought is reduced. And one of the consequences of this is that you may lose the ability to notice that you have lost anything. You agree to give the new med a try, and you start taking it, and then when you see your prescriber again you don’t report any problems because you’ve lost the ability to form thoughtslike “my cognition has changed a lot recently, and the change coincided with the introduction of this new med.” This can go on for years. It did for me and for several people I know. When I finally went off Risperdal – encouraged by my parents, I don’t remember really caring – it suddenly seemed obvious that I’d been cognitively altered for the past five years. I didn’t remember the time before that very well (I had started Risperdal when I was about 10 years old), but there were objective indicators – for instance, I loved reading before Risperdal, and while on Risperdal I don’t think I read a single book cover-to-cover. You’d think I would have noticed that I couldn’t read anymore. Somehow I didn’t, for five years. What did it feel like? It’s hard to remember and also hard to describe. Sort of a passivity. The world acted upon me for mysterious reasons. I did not draw correlations between present and past events, didn’t formulate ideas about the workings of things. The present was simply given; I wasn’t frustrated when it refused to honor my theories. “Reading is hard” was a datum, and was unpleasant, but I was not really surprised by it, or frustrated in the “this wasn’t supposed to happen!” way of abstract-reasoning-creatures. It was a given datum and all I did was hope that given data would be pleasant and not unpleasant. I think people should know that antipsychotics can do this. They still may be worth trying, in certain situations. But taking an antipsychotic is a special sort of decision, one that interferes with decision-making itself, like choosing to listen to the Sirens.

There are also cases of antipsychotics causing autistic catatonia, in which an autistic person, upon treatment with antipsychotics, suddenly loses speech and motor skills. See examples: personal narrative, case study, case study.

So, a natural question is: does this happen often? Do antipsychotics actually cause cognitive problems?

And here I’m referring to long-term cognitive problems. Many medications, including most atypical antipsychotics, are sedating; nobody thinks as clearly when they’re sleepy. But when you stop taking a sedative, you generally become alert again. Do antipsychotics have any permanent effects?

Now, a major confounder is that schizophrenia causes cognitive impairment in itself, and antipsychotics seem to slightly relieve those problems.

Overall, atypical antipsychotics seem to help cognition in schizophrenia

One study of 533 patients having their first psychotic episode and randomized to either risperidone or haloperidol found that, on both drugs, there were slight but significant improvements in most cognitive tests after 3 months of treatment and patients did not significantly worsen on any tests.[1]

The CATIE trial, a randomized trial of 1460 schizophrenics given various antipsychotics, found significant (p < 0.001) improvement in a composite score consisting of speed, reasoning, working memory, verbal memory, and vigilance on all antipsychotic meds.[2]

There are dozens of studies like this. A meta-study found that various atypical antipsychotics were found to improve cognitive functioning in roughly half of studies, most of which were short-term (6 weeks).[3]

Typical Vs. Atypical Side Effects

“Typical” antipsychotics are older drugs, like haloperidol, whose primary effect is dopamine antagonism, while “atypical” antipsychotics are newer drugs, like risperidone, olanzapine, clozapine, and quetiapine, with a wider variety of targets including serotonin agonist, anticholinergic, and antihistamine effects. The atypical drugs are often believed to be safer because they aren’t as likely to cause the motor disorders (extrapyramidal effects and tardive dyskinesia — that is, Parkinson’s-like stiffness and involuntary twitching movements) that the older drugs did, but the newer drugs often have other side effects (like sedation and large amounts of weight gain).

Clozapine is associated with an average of 14-25 pounds of weight gain over a period of several months of treatment; over 50% of patients become overweight when treated with clozapine. A year of high-dose olanzapine causes an average of 26 pounds of weight gain. Risperidone and quetiapine are associated with a weight gain of 4-5 pounds over the course of 5-6 weeks, and remaining stable over long-term use.[4] At the higher end of weight gain, this is no longer a cosmetic issue, but a serious diabetes risk.

Recently, it’s been observed that “atypical” antipsychotics can cause motor problems too, and their safety advantages have been overstated.

The CATIE study found that 8% of patients on olanzapine or risperidone had extrapyramidal symptoms. All agents, typical and atypical, had rates of tardive dyskinesias of 13-17% after a year of follow-up. Akasthisia rates for atypical antipsychotics are in the 10-20% range, compared to 20-52% with typical neuroleptics.[5]

While older studies found that atypical antipsychotics had lower rates of extrapyramidal effects than typical antipsychotics, these studies were comparing the new drugs to high-dose haloperidol, and the difference disappears when you compare to low-dose haloperidol or other typical antipsychotics (such as perphenazine, whose side effects are milder.) The CATIE trial, which randomized schizophrenics to olanzapine, quetiapine, risperidone, perphenazine, or ziprasidone, found no differences in the incidence of extrapyramidal side effects. 12-month Parkinsonism rates were 37-44% for the four atypical antipsychotics and 37% for perphenazine. Akasthisia rates were 26-35% for the atypical antipsychotics and 35% for perphenazine. Tardive dyskinesia was rarer, but also not different — 1.1%-4.5% for the atypical antipsychotics and 3.3% for perphenazine.[6]

In a meta-study, second-generation antipsychotics had significantly less use of antiparkinson medication than haloperidol (RR’s 0.17 for clozapine to 0.7 for risperidone), but not significantly less compared to low-potency typical antipsychotics (like perphenazine). Atypical antipsychotics caused significantly more weight gain than haloperidol, but not compared to low-potency typical antipsychotics. Atypical antipsychotics caused the same amount of sedation as haloperidol and low-potency typical antipsychotics — except that clozapine causes more sedation than everything else.[7]

In other words, it’s definitely not true that the new drugs are safer than the old drugs across the board. Lower doses or better choices in the old drugs would have a comparable or strictly better side effect profile.

As a rough rule of thumb, the stronger the antihistamine effects, the more sedation and weight gain (that’s clozapine and olanzapine), and the stronger the dopamine-antagonist effects, the more movement disorders there are (that’s haloperidol and risperidone).

Evidence that Antipsychotics Impair Cognitive Abilities

While the majority of studies of antipsychotics find improvements or no change on cognitive tests, there are some exceptions, particularly on tests that have to do with spatial or procedural learning.

A study of 25 patients, after being on risperidone for 6 weeks, and throughout a 1-year follow-up period, found that risperidone worsened spatial working memory in first-episode schizophrenia. [8]

Procedural learning is impaired after months of treatment with haloperidol and risperidone — schizophrenic patients are slower to learn the Tower of Toronto task (though no difference is apparent after 6 weeks of treatment). Olanzapine caused much less cognitive impairment (p < 0.001).[9]

A comparison of treatment-naive first-episode schizophrenics vs. schizophrenics treated with risperidone for six weeks found that the untreated patients were no worse at a procedural learning task than controls, while the treated patients were significantly worse. This indicates that the medication, and not the schizophrenia, is responsible for the impairment.[10]

In a study of 35 schizophrenic and 45 control patients given a procedural learning task, the patients randomized to haloperidol performed worse than controls, while those randomized to risperidone or clozapine did not.[12]

In a study of 20 patients on haloperidol, 20 on risperidone, and 19 healthy controls tested on psychomotor tests related to driving ability, the medicated patients were significantly worse than controls on all tests, and haloperidol was worse than risperidone.[11]

Note that procedural learning — remembering how to complete a task, usually physical/motor, by practice — is associated with activity in the striatum and basal ganglia, the part of the brain that produces dopamine. This seems to fit with the fact that antipsychotics, in particular the most dopamine-inhibiting ones, particularly impair procedural learning.

Evidence that Tardive Dyskinesia Comes With Cognitive Impairment

Out of 28 studies identified in a meta-study, 22 reported patients with tardive dyskinesia to be more impaired along at least one cognitive measure. The most common findings were an association with decreased orientation and memory (13 studies). The finding persists even in studies that controlled for anticholinergic side effects. Orofacial tardive dyskinesia seems to be especially associated with cognitive impairment (beta=0.23 of association with performance on the Trail Making Test, a measure of executive function and task switching).[13]

If cognitive dysfunction is a symptom of tardive dyskinesia, that supports the hypothesis that antipsychotic drugs cause cognitive dysfunction.

Animal Evidence that Antipsychotics Cause Cognitive Impairment

Animal studies give a usefully different perspective than human studies because you can ethically give antipsychotics to healthy animals. It may be that antipsychotics both remediate the cognitive problems caused by schizophrenia and cause additional cognitive problems of their own; with animals, you can see the latter in isolation.

Monkeys develop working memory deficits after 1-4 months of haloperidol administration (P = 0.0000004) and recover when given a D1 agonist.[15]

If you give a rhesus monkey haloperidol, it performs worse on a working-memory task (in which, if you can remember which window had a flashing light earlier, you get a treat when you stick your face in), and the higher the dose, the worse the accuracy.[16]

Haloperidol, olanzapine, risperidol, quetiapine, and clozapine all worsened marmosets’ performance at an object-retrieval task relative to baseline. Lurasidone, on the other hand, improved performance.[17]

Evidence that Antipsychotics Shrink Brains

A meta-study of longitudinal MRI effects of antipsychotics on brain volumes found that ventricular volumes increased 7.7-10.9% in treated patients, compared to 1.4% in controls; and that gray-matter or whole-brain volume decreased 1.2-2.9% per year in patients compared to 0.4 to 1% in controls. [Note that ventricles are fluid-filled spaces in the skull cavity: growing ventricles means a shrinking brain.]

But is this just the result of schizophrenia itself causing brain damage? The evidence suggests not. Two studies of drug-naive patients showed a decrease in brain volume after onset of antipsychotics; two showed no effect. Studies of chronically ill, untreated patients in India show no difference in brain volume vs. controls. There’s no difference in volume in the brains of “high-risk” (pre-psychosis) patients compared to controls, including in the subgroup that went on to develop psychosis. It may be that the reduction in brain volume that has usually been associated with schizophrenia is instead caused by antipsychotic use.[14]

Longer-term and higher-dose use of antipsychotics is associated with more gray matter and white-matter shrinkage, even after adjusting for illness severity, substance abuse, and follow-up duration.[18]

Long-term (17-27 month) exposure to antipsychotics (olanzapine and haloperidol) in macaque monkeys resulted in an 8-11% reduction in brain weight.[19]

The fact that antipsychotic-naive schizophrenics do not show a progressive decline in brain volume, and the fact that treating macaques with antipsychotics does cause a decline in brain volume, has led psychiatrist Joanna Moncrieff to argue that antipsychotics do not exert a “neuroprotective” effect on schizophrenia, and that schizophrenia is not a degenerative brain disease — instead, she believes that antipsychotics treat symptoms and also cause much of the brain damage we observe in schizophrenics.[20]

Personal Views

Before I went to the literature on this, I had a pretty negative view on antipsychotics, heavily colored by the personal stories I’ve heard of them working out very badly, and the rare cases of severe side effects like neuroleptic malignant syndrome. My view was also colored by the fact that they’re often used on children and psychiatric inpatients as a coercive mechanism, against the will of the patients, and whether or not they have any medically beneficial effect. My sympathies are always going to be with the victims of coercion who have, in many cases, pleaded eloquently to just be let alone.

On the other hand, schizophrenia is really bad. And, from what I can tell, we can be quite confident that antipsychotics reduce the positive symptoms (delusions and hallucinations). I can believe there are situations where the benefits outweigh the costs.

I think the evidence that antipsychotics, including atypical antipsychotics, can cause cognitive impairment is pretty compelling.

Do they cause net cognitive impairment in schizophrenics? I don’t know. Maybe they reduce negative symptoms enough to balance out the cognitive impairment.

Do they cause irreversible cognitive impairment? I don’t know. I don’t think we have human evidence of what happens to brains when people go off antipsychotics, or take a dopamine agonist.

Is taking antipsychotics worse, or better, than leaving psychosis untreated? Can you split the difference by taking lower dosages or getting off meds sooner? I have no idea how I would even begin to answer this question, and the answer probably depends a lot on individual values.

Here’s stuff that I do think is sensible to do (keep in mind, I am not a doctor or any kind of psych professional):

Think about the tradeoffs of antipsychotics before you have a psychotic break. In some states, including California, you can write up a psychiatric advance directive in which you can specify what to do in the event you lose your mind, including medications you are not to be given.

Look up psychiatric meds that you’re prescribed and see what they do. Sometimes antipsychotics will be prescribed for things besides psychosis, like depression or Tourette’s. Sometimes they work for those things! But they have the same kinds of side effect risks that they always do, and doctors don’t always tell you that. Abilify? Is an antipsychotic! It can cause extrapyramidal side effects! It’s surprisingly common for people not to get told things like this.

Don’t take a judgmental, one-size-fits-all attitude unless you have correspondingly incredible data. “Always meds!” and “Never meds!” are terrible oversimplifications. We don’t know what’s going on yet, so in the meantime, all anyone can do is to try to make the best judgments they can under conditions of colossal uncertainty (and often great stress).



References

[1]Harvey, Philip D., et al. “Treatment of cognitive impairment in early psychosis: a comparison of risperidone and haloperidol in a large long-term trial.” American Journal of Psychiatry 162.10 (2005): 1888-1895.

[2]Keefe, Richard SE, et al. “Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE Trial.” Archives of general psychiatry 64.6 (2007): 633-647.

[3]Meltzer, Herbert Y., and Susan R. McGurk. “The effects of clozapine, risperidone, and olanzapine on cognitive function in schizophrenia.” Schizophrenia bulletin 25.2 (1999): 233-256.

[4]Nasrallah, H. “A review of the effect of atypical antipsychotics on weight.” Psychoneuroendocrinology 28 (2003): 83-96.

[5]Shirzadi, Arshia A., and S. Nassir Ghaemi. “Side effects of atypical antipsychotics: extrapyramidal symptoms and the metabolic syndrome.” Harvard Review of Psychiatry 14.3 (2006): 152-164.

[6]Miller, Del D., et al. “Extrapyramidal side-effects of antipsychotics in a randomised trial.” The British Journal of Psychiatry 193.4 (2008): 279-288

[7]Leucht, Stefan, et al. “Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis.” The Lancet 373.9657 (2009): 31-41.

[8]Reilly, James L., et al. “Adverse effects of risperidone on spatial working memory in first-episode schizophrenia.” Archives of General Psychiatry 63.11 (2006): 1189-1197.

[9]Purdon, Scot E., et al. “Procedural learning in schizophrenia after 6 months of double-blind treatment with olanzapine, risperidone, and haloperidol.” Psychopharmacology 169.3-4 (2003): 390-397.

[10]Harris, Margret SH, et al. “Effects of risperidone on procedural learning in antipsychotic-naive first-episode schizophrenia.” Neuropsychopharmacology 34.2 (2009): 468-476.

[11]Soyka, Michael, et al. “Effects of haloperidol and risperidone on psychomotor performance relevant to driving ability in schizophrenic patients compared to healthy controls.” Journal of psychiatric research 39.1 (2005): 101-108.

[12]Scherer, Hélene, et al. “Procedural learning in schizophrenia can reflect the pharmacologic properties of the antipsychotic treatments.” Cognitive and behavioral neurology 17.1 (2004): 32-40.

[13]Waddington, J. L., et al. “Cognitive dysfunction in schizophrenia: organic vulnerability factor or state marker for tardive dyskinesia?.” Brain and cognition 23.1 (1993): 56-70.

[14]Moncrieff, J., and J. Leo. “A systematic review of the effects of antipsychotic drugs on brain volume.” Psychological medicine 40.09 (2010): 1409-1422

[15]Castner, Stacy A., Graham V. Williams, and Patricia S. Goldman-Rakic. “Reversal of antipsychotic-induced working memory deficits by short-term dopamine D1 receptor stimulation.” Science 287.5460 (2000): 2020-2022.

[16]Bartus, Raymond T. “Short-term memory in the rhesus monkey: Effects of dopamine blockade via acute haloperidol administration.” Pharmacology Biochemistry and Behavior 9.3 (1978): 353-357.

[17]Murai, Takeshi, et al. “Effects of lurasidone on executive function in common marmosets.” Behavioural brain research 246 (2013): 125-131.

[18]Ho, Beng-Choon, et al. “Long-term antipsychotic treatment and brain volumes: a longitudinal study of first-episode schizophrenia.” Archives of general psychiatry 68.2 (2011): 128-137.

[19]Dorph-Petersen, Karl-Anton, et al. “The influence of chronic exposure to antipsychotic medications on brain size before and after tissue fixation: a comparison of haloperidol and olanzapine in macaque monkeys.” Neuropsychopharmacology 30.9 (2005): 1649-1661.

[20]Moncrieff, Joanna. “Questioning the ‘neuroprotective’hypothesis: does drug treatment prevent brain damage in early psychosis or schizophrenia?.” (2011): 85-87.