One of the common considerations when prescribing haloperidol is whether it will prolong the QT interval. This is a measure of the heart rhythm on the EKG that correlates with one’s risk for serious arrhythmias such as torsades de pointes.
Earlier this year, van den Boogaard et al published one of the largest RCTs to compare haloperidol against placebo (700+ people in both groups).
Their main finding was that prophylactic haloperidol was not helpful for reducing the rate of delirium or improving mortality.
But one of their most interesting results was the safety data. This showed that their dose of haloperidol had no effect on the QT interval and caused no increased rates of extrapyramidal symptoms. Their regimen was haloperidol IV 2 mg every 8 hours, which is equivalent to ~ 10 mg oral haloperidol in one day.
The maximum QT interval was 465 ms in the 2 mg haloperidol group and 463 ms in the placebo group, a non-significant difference with a 95% CI for the difference of -2.0 to 5.0.
Notably, they excluded people with acute neurologic conditions (who may have been more likely to have cardiovascular problems) and people with QTc already > 500 ms, which makes generalization of this finding to those groups a bit tricky.
As I’m trying to learn more about antidepressants, I found it interesting to make a visualization of the receptor binding profiles of some of the better characterized ones, so I thought I would post it here.
Some of these medications aren’t widely used anymore or were never pursued for development, so they are also a window into the history of psychiatry and what could have been. This is how the meds cluster based on their receptor binding:
One interesting thing about these clusters is that they cut the medications into groups distinguished by their chemical/drug classes:
Group #1: TeCAs like mirtazapine and one TCA, doxepin; o
Group #2: TCAs like amitryptiline and one TeCA, amoxapine
Group #3: SSRIs/SNRIs, like fluoxetine and venlafaxine
From what I understand, the researchers designed the trial to mimic what might happen in a realistic clinical setting.
A patient diagnosed with major depressive disorder (MDD) might be first started on a first-line drug (citalopram). If that didn’t work (because the side effects were untolerable, or the symptoms persisted), then another drug would be chosen, and so on. Here is their algorithm:
They used a unique randomization strategy, as participants in Level 2 could choose to opt out of the randomization blocks that entailed a) switching off of citalopram, b) augmenting citalopram with a different drug, and/or c) using cognitive therapy.
From the numbers above, you can see that most common option was for participants to opt out of cognitive therapy. This is probably in part accounted for by a selection bias for participants who would enter the citalopram-based trial in the first level.
One of the main outcomes was the remission rates from depression (defined as QIDS-SR16 score of <= 5) at the various stages:
For step 1, the remission rate for those not treated for their current episode was 43%, vs 36% for those already treated for their current episodes
For step 2, the remission rate was 30%
For step 3, the remission rate was 14%
For step 4, the remission rate was 13%
Assuming that none of the participants existed the study and stayed in treatment, the theoretical remission rate after a maximum of four treatment steps was 67%
They also looked at the 12-month follow up of these same participants. Of those, the proportion without a relapse (defined as QIDS-SR16 >= 11) was ~50% in the participants who had a remission of symptoms following step 1, and ~ 33% in the participants who had a remission of symptoms following step 2.
In the 1940s two Danish researchers, Erik Jacobsen and Jens Hald, tested a series of substances in an attempt to identify drugs that might rid the body of intestinal worms. After one of them worked in rabbits, Jacobsen tried it on himself, as he had a fun little habit of trying all of his invented drugs on himself.
“During the course of self-experimentation” as Larimer reports, both Jacobsen and Hald noted this substance — called disulfiram — led to a substantial increase in their sensitivity to the toxic effects of alcohol.
In late 1947 and 1948, Oluf Martensen-Larsen, an expert on the treatment of alcoholism, was able to convince his colleagues to allow him to try disulfiram in the treatment of alcohol abuse. In this classic paper, he reported on 83 patients that he had treated with disulfiram (also called Antabuse) for the treatment of their alcohol addiction.
At the time the mechanism was not known, but it was known that giving the drug prophylactically led people to become violently ill with hangover-like effects of alcohol. It is now almost certain that its effects are due to the inhibition of aldehyde dehydrogenase, which causes acetaldehyde to build up in the blood stream following alcohol consumption and cause all sorts of unpleasant toxicity.
In cultured cortical neurons, acetaldehyde causes a substantial loss of MAP2-positive neuronal processes, indicative of the fact that the toxicity of acetaldehyde does not spare the CNS:
One of the patients he described as having a successful reaction to the treatment was a middle-aged woman. After starting on disulfiram, she began to blush after taking only a mouthful of liquor. As Martensen-Larsen reports, “Her abstinence might be explained by her desire to avoid the humiliation associated with the blushing, but she insists that this is not the deciding factor, and that she has lost the taste for wine and spirits.”
Overall, he classifies 32/83 (39%) of patients as successes, 29/83 (35%) as partial successes as long as their blood and urine checks indicated that they will still on the drug, 13/83 (16%) as successes only as long as the physician can successfully encourage them to stay on the drug, and 9/83 (11%) as not responding to the drug, at least in because they refused to continue on it.
Disulfiram is still used today as a part of a comprehensive treatment for alcohol addiction that includes psychosocial factors as well.
This classic 2009 review paper by Fletcher and Frith, currently cited 456 times, attempts to explain the two major positive symptoms of schizophrenia, hallucinations and delusions, as due to a common high-level cognitive mechanism.
But first, they consider one of the simplest hypotheses: might people with schizophrenia have disordered reasoning in general? The authors reject this hypothesis because patients with schizophrenia do not have problems with logic in general; at least in the n = 32 study they cited, control as opposed to deluded people were actually slightly more likely to fall for fallacies in logical questions.
Instead,Fletcher and Frith’s hypothesis relates to a failure to correctly perform conditional reasoning.
As they point out, stimuli that do not challenge a belief are usually ignored, which is often necessary in order to deal with the large number of stimuli in one’s environment.
Intriguingly, in animals, this prediction error-dependent learning is highly dependent on the dopaminergic system. And there is a wealth of evidence showing that the dopamine system is implicated in schizophrenia, including the ventral striatum.
Their hypothesis, then, is that there is a quantitative divergence in the prediction error-dependent learning for every day stimuli in schizophrenia.
This leads normal stimuli to feel unduly important and thus makes properly attending to one’s environment challenging. This can explain delusions, because people must attempt to explain why those stimuli feel so surprising.
This could also make internal thoughts (which are perceived stimuli just like any other) appear more likely to be under external rather than internal control, because they are imbued with a particular sense of surprisingness. This, of course, can explain hallucinations.
Of course, this is just a model and is probably flawed in various ways, but it’s a pretty thorough one and worthy of consideration.
Fletcher PC, Frith CD. Perceiving is believing: a Bayesian approach to explaining the positive symptoms of schizophrenia. Nat Rev Neurosci. 2009;10(1):48-58.
Classic Paper: Elkes J, Elkes C. Effect of chlorpromazine on the behavior of chronically overactive psychotic patients. Br Med J. 1954;2(4887):560-5
In 1950, a group of anesthesiologists in France were trying to find new drugs for anesthesia. They tested the newly synthesized drug chlorpromazine on animals (dogs, rodents, and mice) and found that it led to drowsiness and indifference to aversive stimuli.
Since this was the 1950’s, they were able to quickly try it on people as a booster for anesthesia. They found that people who took chlorpromazine did not lose consciousness, but it did have a profound calming effect. Quickly people thought of trying it on patients with psychosis, for which the available treatments were very limited.
This study by Joel Elkes and Charmian Elkes, who were married, was the first to report a placebo-controlled trial on the effect chlorpromazine in psychosis. It appears that the majority of the data collecting and work was done by Charmian, rather than Joel.
They used a classic crossover study design, testing each patient on both chlorpromazine and an inert placebo (although they do not use the word “random”). They used notes written by the doctors and nurses that were blind to the treatment type to decide whether or not the patient had improved.
Of the 23 patients with a type of psychosis in their study, 7 (30%) showed “definite improvement” when they were taking the drug compared to when they were not, 11 (48%) showed “slight improvement,” and 5 (22%) showed “no improvement.”
Other interesting notes from the paper:
They describe the effect of chlorpromazine as symptomatic, since the psychosis itself did not abate: “the essentially symptomatic nature of the response has already been stressed, and cannot be overemphasized. Although affect became more subdued, and attitude and behaviour reflected this improvement, the ingrained psychotic thought disorder seemed to be unchanged.”
Because of their detailed records, they noted significant weight gain in 9/23 of the patients (in all of whom the drug led to at least a slight improvement), which has been borne out in both chlorpromazine and in the drug class in general: almost all antipsychotics result in weight gain. Of this effect, they say: “For the present we are inclined to attribute this to improved eating habit as the patients became less tense, less preoccupied, or less assaultive; though more direct metabolic effects of the drug cannot be excluded.”
They also tried it on 3 patients with senile dementia, all of whom had “no improvement.” This is yet another example of how Alzheimer’s is where drug discovery goes to die.
Notably, the mechanism remained pretty unknown until the mid-1960s, when it was shown that dopamine metabolites correlated with the chlorpromazine dose given to animals. In 1976, Seeman et al. found a nearly perfect correlation (on the log-log scale) between the ability of antipsychotic drugs to displace haloperidol from binding to the dopamine receptor and the clinical dose required for its effect.
Interestingly, you can see in this figure that chloroprazamine actually has one of the less strong dopaminergic affinities and higher doses required for controlling schizophrenia. Despite this, it and its derivatives have on to become some of the most game-changing psychiatric drugs of all time.
Shen WW. A history of antipsychotic drug development. Compr Psychiatry. 1999;40(6):407-14.
Elkes J, Elkes C. Effect of chlorpromazine on the behavior of chronically overactive psychotic patients. Br Med J. 1954;2(4887):560-5.
Bak M, Fransen A, Janssen J, Van os J, Drukker M. Almost all antipsychotics result in weight gain: a meta-analysis. PLoS ONE. 2014;9(4):e94112.
Seeman P, Lee T, Chau-wong M, Wong K. Antipsychotic drug doses and neuroleptic/dopamine receptors. Nature. 1976;261(5562):717-9.
Classic Paper: Cade JF. Lithium salts in the treatment of psychotic excitement. Med J Aust 1949; 2:349-352
Prior to 1949, treatments for mania were limited. That year, John Cade published a paper showing the usefulness of lithium in treating patients with mania (“psychotic excitement”).
Interestingly enough, the finding was apparently a surprise to Cade. He was studying guinea pigs in order to see whether uric acid added to the convulsive toxicity of urea, but he needed to find a way to make uric acid soluble in water to be able to inject it into the guinea pigs. (Confusingly enough, urea and uric acid have almost nothing to do with one another chemically.)
For this, he used the lithium salt of urate, and was surprised to find that it was protective against the urea-induced convulsions. He then injected lithium carbonate alone into guinea pigs, and noted that after a couple of hours, they became lethargic and unresponsive to stimuli.
Skipping straight from this effect in guinea pigs (not even a disease model!! — this would never be allowed today) to humans, Cade then reports on 10 cases of patients with mania who were successfully treated with lithium, including longitudinal cases of chronic mania where the mania subsided during lithium treatment and recrudesced when lithium was discontinued.
Other interesting aspects of this paper:
Cade notes that historically, water from certain wells was associated with improvements in mental illness, and speculates that “it is very likely that their supposed efficacy was a real efficacy and directly proportional to the lithium content of the waters.”
Cade notes that lithium treatment “would be much preferred” to what is usually now considered the cruel treatment of prefrontal leucotomy, even though this (1949) was the year that the Nobel prize was awarded for it, and its use continued into the mid-1950s.
All of the cases reported on were men between ages 40 and 65 years old, indicating a total lack of evidence for generalization of the effect across more diverse patient populations.
Recent meta-analysis (2013) has shown that antipsychotics are more effective than lithium in the treatment of acute mania (e.g., the standardized mean difference in manic symptoms for haloperidol is -0.56, while for lithium it is -0.37), but lithium is still often used in combination with antipsychotics in the treatment of mania.
Overall, this short paper is among the best I’ve read in terms of scientific puzzle solving, although you could argue that Cade got lucky.
Cade JF. Lithium salts in the treatment of psychotic excitement. 1949. Bull World Health Organ. 2000;78(4):518-20.
Cipriani A, Barbui C, Salanti G, et al. Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis. Lancet. 2011;378(9799):1306-15.
Doig MT, Heyl MG, Martin DF. Lithium and mental health. J Chem Educ. 1973;50(5):343-5.