From the Editor

Singer Olivia Rodrigo may have a catchy song about getting a driver’s license and Ariana Grande has a ditty about past relationships, but, in the late 1960s, the Rolling Stones wrote a whole song about diazepam, “Mother’s Little Helper.” The choice of topic isn’t so surprising: between 1968 and 1982, diazepam was the most prescribed medication in the United States and commonly used around the world.

But the pendulum has swung in the other direction. Today, we hesitate on prescribing benzodiazepines like diazepam, in part because of concerns about substance misuse and dose escalation. But how addictive are these meds? How significant is dose escalation over time? Though smaller studies have sought to answer these questions, Dr. Thomas Wolff Rosenqvist (of the University of Copenhagen) and his co-authors drew on Danish databases in an important, new study published in The American Journal of Psychiatry. They looked at two decades of data involving almost a million Danes who have used benzodiazepines. “A limited portion of the population that received benzodiazepines prescriptions were classified as continuous users, and only a small proportion of this group escalated to doses higher than those recommended in clinical guidelines.” We consider the study, the editorial that accompanies it, and the implications for practice.

Denmark: beautiful buildings, rich history, great data on benzodiazepines

In this week’s other selection, Michael Dickson (of the University of South Carolina) writes about the symptoms of schizophrenia. Dickson, who is a professor of philosophy, touches on philosophical concepts but, also, on personal experience – as an individual with the illness. In a paper published by Schizophrenia Bulletin, he recalls a psychotic episode, his ongoing symptoms, and how he came to terms with the disorder. “This attitude has made life better and has made the ‘near-collapses’ much rarer.”


Selection 1: “Long-Term Use of Benzodiazepines and Benzodiazepine-Related Drugs: A Register-Based Danish Cohort Study on Determinants and Risk of Dose Escalation”

Thomas Wolff Rosenqvist, Marie Kim Wium-Andersen, Ida Kim Wium-Andersen, et al.

The American Journal of Psychiatry, March 2024

Benzodiazepine receptor agonists (BZRAs), which include benzodiazepines and Z-drugs, are the most commonly used drugs for treating insomnia and anxiety. However, tolerance to and abuse of BZRAs have been described over the years. Consequently, health authorities in many countries have restricted prescription of these drugs through guidelines recommending only short-term treatment, as long-term treatment may be less effective as a result of tolerance and carries a risk of dependence. In 2020, the U.S. Food and Drug Administration updated the boxed warning on all BZRAs to explicitly ‘address the serious risks of abuse, addiction, physical dependence, and withdrawal reactions’. This has initiated an intense discussion of risks and benefits of BZRAs and whether these regulations are based on sufficient clinical evidence or might lead to stigmatization of BZRA users and motivate physicians to avoid these drugs, although long-term use may be warranted in some situations. Thus, whereas more than 40 previous studies have explored the prevalence and characteristics of long-term BZRA use (for more than 1 year), relatively little is known about the potential risk of dose escalation – that is, when users require a higher dose of a given drug over a given period, which is seen as a proxy for development of tolerance. A recent study in Finnish adults found that around 11% of incident users of Z-drugs or the most commonly prescribed benzodiazepine (oxazepam) had a long-term use for more than 7 years after start of treatment, whereas earlier studies from Sweden and the Netherlands reported rates above 30% for long-term users after 8 years…

So begins a paper by Rosenqvist et al.

Here’s what they did:

  • They drew from several databases, including from the Danish Civil Registration System (to identify all individuals 20 – 80 years of age living in Denmark in 2000) and the Danish National Prescription Registry (to identify those who redeemed benzodiazepines prescriptions from January 1, 2000, to December 31, 2020).
  • “For each drug class, we calculated long-term use for more than 1 or 7 years, and dose escalation measured as increase in dose to a level above the recommended level.” 
  • Different variables were considered, including clinical and sociodemographic.
  • Statistical analyses were done, including logistic regression.

Here’s what they found:

  • A total of 950 767 individuals started on a benzodiazepine during the study period.
  • Median age. The median age was 55 years at med initiation.
  • Use. 46% had only a single purchase and 22% had more than five. The median treatment duration was 273 days.
  • Long-term use. The overall risk of use for more than one year was 15%. The proportion was highest among individuals who initiated treatment with Z-drugs (17.8%) and lower for users of anxiolytic and hypnotic benzodiazepines (13.1% and 9.8%, respectively). 
  • Longer-term use. 3% used longer than seven years. (!!)
  • Dose. Among those who had at least three years of continuous use, “there was no indication of dose escalation, as the median dose remained relatively stable.”
  • Risk factors. “Psychiatric comorbidity, especially substance use disorder, was associated with higher risk of long-term use and dose escalation.”

A few thoughts:

1. This is an important study, with a robust data set, stretching over many years, and published in a major journal.

2. The findings in a sentence: just 15% of patients used benzodiazepines for more than a year and only 3% for longer than seven; doses didn’t tend to increase with time.

3. Is that different than the perception? The authors argue yes: “Our study does not support the widespread belief that BZRAs are associated with long-term use and dose escalation…”

4. The paper runs with an editorial by Stephen B. Soumerai (of Harvard University) and his co-authors. They begin: “The potential for misuse of benzodiazepines and benzodiazepine-related drugs… has been a source of controversy for over five decades.”

Stephen B. Soumerai

They aren’t surprised by the Rosenqvist et al. study. “These findings are largely consistent with decades of smaller studies in several countries: Our early study of BZRA dose escalation among 2,440 Medicaid recipients in New Jersey with at least 2 years of reported use that found that 1.6% of patients escalated to high doses. A study of 81,945 BZRA recipients in Norway reported that only 0.9% ended up using >2 defined daily doses. And a study of 12,598 patients in Canada recorded that 3.1% of patients who were prescribed benzodiazepines for at least 2 years escalated to doses higher than 40 diazepam milligram equivalents.”

They argue that hesitation around benzodiazepines stems from bad science. “Much of the previous research on outcomes of BZRAs (and other psychoactive medications) exaggerated drug harms on the basis of weak cross-sectional pharmacoepidemiologic designs that did not control for confounding by indication. This common bias occurs when physicians preferentially treat sicker or older patients. Conditions such as dementia, drug abuse, and other chronic illnesses often cause the adverse outcome, not the treatment itself. These biases are often hidden because sickness and frailty are poorly measured in common research and insurance databases.”

They conclude: 

“The Rosenqvist et al. study, the largest and longest to date, should put an end to the unfounded assertions that appropriate BZRA prescribing often leads to dose escalation and drug misuse.”

The editorial can be found here:

5. Like all studies, there are limitations. The authors note several, including a lack of completeness of primary care-related data (minor). And, of course, the data set itself – impressive as it is – draws from one country and may not be generalizable to other populations (not minor).

6. Has the pendulum swung too far? This study suggests that some of the fears of benzodiazepines have been overstated. Of course, I’m not advocating a Rolling Stones’ style enthusiasm for the drug class; caution is appropriate, particularly for those patients with a substance use history. 

The full AJP paper can be found here:

Selection 2: “Coming to Terms with Hallucinations: From Vexing Uncertainty to Intellectual Humility”

Michael Dickson

Schizophrenia Bulletin, 22 January 2024 Online First

I am a 55-year-old husband, father, friend, and professional philosopher. In 1992, as a graduate student at Cambridge University, a porter found me amongst the cows in the meadows of King’s College, after being there for 2 or 3 days. I was in bad physical shape, having eaten nothing, and apparently getting water from the river. He asked what I was doing. I replied: ‘I’m solving a problem about stochastic calculus.’ This statement was true, but did not answer his question. He took me to the hospital, where I remained for some weeks.

It wasn’t the first time that I was psychotic, but it was, maybe, the first time that anybody noticed, the first time that I was unable to hide it from others, and therefore from myself. What follows is an abbreviated account of how I learned – haltingly, with setbacks, over the years – to cope with chronic schizophrenia. There have been near-collapses, but I have managed to keep a job for 30 years. I have not, until recently, been open about my diagnosis (excepting my wife and a close friend).

So begins an essay by Dickson.

He attributes his success to support. “The most important part of my story is people. The reason that I am not in prison, homeless, or dead, is a few people who genuinely respect and care for me, and I them, not least through what some philosophers call ‘hermeneutical justice.’ Without these people, there would be no ‘coping,’ and the rest of what follows could never have happened.”

He relates his experiences with symptoms. He notes that he has heard music since childhood, but “musical hallucinations don’t disturb me.” In contrast, he describes his auditory hallucinations. “Voices are a different story – they are rarely intrinsically disturbing, but uncertainty about their origin is. For some time, it felt important to figure out whether the voices were coming from people who are physically present. My doctor called it ‘reality-check.’ Sometimes reality check is easy, eg, if there is a voice whispering in my ear but nobody near my ear. But often reality check is very difficult. In a crowded place, hearing a conversation, does one ask people whether they just said anything? Does one snoop around to find the source of the talking? Does one stare at people’s mouths to see whether they are talking?”

He writes about a particular episode that “changed my approach to hallucinations.” He explains: “The scene is a cold, dark, morning, in a coffee shop. There are no other customers. I order my coffee and pastry, sit down, and start working. Soon I hear a conversation. Normally I would have done my reality check, and doing so would have been easy (it’s a small shop), but I felt confident that nobody apart from the sole employee and myself were present, and the voices were not inherently disturbing, so I kept working. Then one of the voices said my name, directly to me. Hearing my name almost always gets my attention, and I turned around, although still expecting to see nothing, but there were two people behind me – real people! – and I knew one of them; he had recognized me and was saying hello.”

He describes a small breakthrough. “I suppose that sort of thing had happened before, but in that moment I realized something that I had not realized before: It is not important to know where the voices are coming from.”

He suggests similar thinking with his thought broadcasting – “for some time I did worry that others might hear my thoughts.” He continues: “I tried hard to think nice thoughts, or to think nothing. After extensive self-reflection, I realized that something slightly different is going on. I realized that it is difficult to tell the difference between speaking out loud and thinking. When I’m focused, I can tell the difference by paying careful attention to my body – especially my lips and throat – but one cannot always focus in that manner, and the resulting uncertainty about what has, or has not, been said out loud can kindle anxiety. Many of my conversations are laced with uncertainty about what I have said out loud, versus merely thought to myself… After I realized what is going on, I tried to avoid this uncertainty, either by trying not to think or say anything (which is difficult), or by frequently repeating myself (which is obnoxious). More recently, I’ve accepted that it rarely matters whether others have heard me.”

He describes a similar acceptance with mirrors and whether there are cameras behind them – and how he comes to terms with his illness.

“I think of this attitude as a kind of ‘intellectual humility’ because although I do care about truth – and as a consequence of caring about truth, I do form beliefs about what is true – I no longer agonize about whether my judgments are wrong. For me, living relatively free from debilitating anxiety is incompatible with relentless pursuit of truth. Instead, I need clear beliefs and a willingness to change them when circumstances and evidence demand, without worrying about, or getting upset about, being wrong.”

A few thoughts:

1. The paper is honest and insightful. 

2. The first paragraph is particularly moving. Mental illness affects everyone – even graduate students at prestigious universities.

3. He is particularly strong in describing how he has learned to reconcile and reimagine his symptoms, a process that has brought him great relief. His conceptualization of “intellectual humility” is interesting. He explains that the belief in a truth or reality, rather than the truth itself, holds great power, ultimately reducing his anxiety. 

4. The experiences of those with psychosis has been covered in past Readings. In 2022, for instance, we looked at the World Psychiatry paper that took a “bottom up” approach to understanding psychosis, informed by academics, experts, and those with lived experience. You can find it here:

The full Schizophr Bull article can be found here:

Reading of the Week. Every week I pick articles and papers from the world of Psychiatry.