Relationship Between Benzodiazepine Prescription, Aggressive Behavior, and Behavioral Disinhibition: A Case-control Study in a Swiss Prison

Benzodiazepines are commonly prescribed in prisons amidst the controversies surrounding their potential role in causing behavioral disinhibition and aggressive behavior and their association with use and tracking of illicit and addictive substances. The present study aimed to 1) ascertain the relationship between benzodiazepine prescription (including their dosage and duration of use) and aggressive behavior and behavioral disinhibition in prison, and 2) investigate whether there was an association between benzodiazepine prescription, (including their dosage and duration of use) and using and tracking illicit and addictive substances during imprisonment. Data were extracted from the electronic database of an “open” Swiss prison (n = 1,379) over a ve-year period (2010–2015). Measures included benzodiazepine prescription (yes/no), duration of benzodiazepine use and mean dosage, and punishable behaviors (physical and verbal aggression, disinhibited but not directly aggressive behaviors, property damage or theft, substance-related offenses, and rule transgression). Propensity score matching was used to assess the relationship between benzodiazepine prescription and punishable behaviors. Logistic regressions were used to test the relationship of benzodiazepine duration and dosage with punishable behaviors.


Introduction
Benzodiazepines (BZD) are one of the most widely prescribed drugs in WEIRD (Western, Educated, Industrialized, Rich, and Democratic) countries [1][2][3][4]. They are mainly prescribed to treat sleep disorders, anxiety disorders, epilepsy, and withdrawal from certain substances. Their use has been widely debated.
On one hand, BZD act quickly, are very useful in acute settings, and are generally effective. On the other, they have been associated with various adverse effects, including sedation, psychomotor and cognitive impairment, falls and fractures in the elderly, and dependence [5,6]. In addition, individuals with substance use disorders frequently abuse BZD, which is harmful, especially when various illicit drugs and opioids are combined with BZD [7]. In view of these problems, most treatment guidelines do not recommend BZD as rst-line treatment for anxiety and related disorders and suggest that they should only be used short-term [8][9][10]. In contrast, several experts have recently pointed out that such recommendations are based on little empirical evidence and that these guidelines do not adequately re ect the risk-bene t ratio when using BZD [3,4,[11][12][13][14].
If use of BZD is controversial in the general population, the situation is even more complex in prisons, where they are commonly prescribed [15,16]. First, substance use disorders are more common among detained persons than in the general population [17], and smuggling and tra cking of drugs are frequent in prisons around the world [18]. Considering the likelihood of BZD abuse in the context of substance use disorders, it has been suggested that BZD should be entirely avoided or minimally prescribed in prisons [15,[19][20][21]. However, this is problematic, because prisoners would be deprived of a valid therapeutic option [2,22].
Another crucial issue associated with prescribing BZD in prisons pertains to an increased risk of behavioral disinhibition, resulting in aggressive behavior [1,23]. There is a dearth of research on this topic [24], and some studies suggest that the link between BZD use and heightened aggression may only apply to short-acting BZD [25]. Furthermore, violent crime was associated with unusually high doses of BZD [26], whereas there was no increase in impulsive behavior with therapeutic doses of BZD [27]. In a recent study, Albrecht et al [28]. concluded that high BZD doses were not su cient to increase the risk of violence. These disparate ndings make it di cult to understand the role of BZD as a treatment option in the prison setting.
In view of the aforementioned issues and controversies, the present study, conducted in a sample of Swiss detained persons, had two main aims: 1) to ascertain the relationship between BZD prescription and aggressive behavior and behavioral disinhibition in prison; we also aimed to assess the potential effects of the dosage of BZD and duration of their use on aggression and behavioral inhibition during imprisonment; and 2) to investigate whether BZD prescription was associated with using and tra cking illicit and addictive substances.

Study design and participants
This retrospective, cross-sectional study was based on the data on 1,206 persons detained in Realta prison, Kanton Grisons, Switzerland. This is an "open" prison (capacity of 120) for sentenced males who work outside the prison and have up to 36 hours of leave per week. Data for the 2010-2015 period were extracted from the electronic prison database on 1,379 measures (some detained persons were incarcerated multiple times). Approval for conducting the study was received from the Cantonal Research were collected. These were classi ed into ve categories: 1) physical and verbal aggression (assaults and threats made against others), 2) disinhibited, but not directly aggressive behaviors (e.g., slamming doors, swearing), 3) property damage or theft, 4) substance-related offenses (alcohol or illicit drug use or tra cking), and 5) rule transgression (e.g., smoking when not allowed, returning from leave late). We made a binary quali cation (presence/absence) for each category.

Statistical analyses
We rst computed descriptive statistics for all variables. Then, we tested whether punishable behaviors were associated with BZD prescription.
In the rst set of analyses, we used a propensity score matching to minimize the effect of confounding factors and make it possible to compare individuals who received BZD with those who did not receive them. This method is used to estimate the effect of a treatment when relying on observational data and to address the fact that assignment to a treatment is not random. The propensity score matching aims to mimic randomization by matching the treated and untreated groups on a set of predetermined covariables. The propensity score was estimated using a probit regression predicting BZD prescription and including the following factors: age, region of origin (Switzerland/not Switzerland), length of incarceration, type of offense, use of any other psychotropic medication, and use of any medication for somatic diseases. The balancing properties of the propensity score were satis ed. We then matched groups (BZD/no BZD) using nearest neighbor matching ( ll Mahalanobis), allowing multiple neighbors in case of identical propensity scores. The average treatment effect on the treated (ATT) was computed for each punishable behavior used as outcome (sanctions related to physical and verbal aggression, disinhibited, but not directly aggressive behaviors, property damage or theft, substance-related offenses, and rule transgression). Crude and matched associations (before/after propensity score matching) are reported.
In the second set of analyses, we focused on detained persons who received BZD. We computed ve logistic regressions, using as predictors mean dosage and duration of BZD prescription and the same outcomes as the rst set of analyses. For all these models, we controlled for age, region of origin, length of incarceration, type of offenses, use of any other psychotropic medication, and use of any medication for somatic diseases.
For the propensity score analysis, we computed sensitivity analyses using other methods to match groups (covariate adjustment, inverse probability weighting, and strati cation). For the second set of analyses, we performed sensitivity analyses by using the maximum BZD dosage instead of the mean dosage. We also conducted logistic regressions using mean dosage and duration of BZD use coded as zero for detained persons without BZD prescription. Finally, we controlled for the effect of short-versus long-acting BZD. In all cases, the ndings were similar to those reported in the Results section.
Analyses were performed with Stata 15 (propensity score estimation: pscore with no imposition of common support, propensity matching: psmatch2 with option "ties").

Results
Descriptive statistics are reported in   1 Means and standard deviations.
2 Percentages and n. 3 There were 165 missing values for the region of origin (12.0%) and 40 missing values for type of offenses (2.9%). 4 Reported for participants with BZD prescription (n = 290).
A total of 293 (21.3%) detained persons were prescribed BZD during their incarceration (mean duration of BZD use = 91.5 days, mean dosage = 24.0 mg/day diazepam equivalents).
In the analyses of the unmatched sample, detained persons with and without BZD prescription were signi cantly different in terms of the factors included in the propensity score and outcomes (left panel of Table 2). In the matched sample, there was no signi cant difference on any factor included in the propensity score (right panel of Table 2). Thus, BZD prescription was not signi cantly associated with any kind of punishable behavior. With regards to detained persons who were prescribed BZD, the mean dosage of BZD was not associated with any kind of punishable behavior ( Table 3). Duration of BZD prescription was signi cantly associated only with disinhibited, but not directly aggressive behaviors (p = .011). Logistic models were adjusted for age, region of origin (Switzerland/not Switzerland), length of incarceration, type of offenses, prescription of any other psychotropic medication, and prescription of any medication for somatic diseases.

Discussion
The main aim of the present study was to investigate the effects of BZD prescription on aggressive behaviors and behavioral disinhibition in a Swiss prison. When controlling for potentially confounding variables, we did not nd any association between BZD prescription and punishable behaviors that would re ect an increase in aggressiveness or behavioral disinhibition. This suggests that control variables might have captured a previous tendency towards aggressive behavior (re ected by the type of offenses) and psychiatric disorders associated with aggressiveness or disinhibited behaviors (re ected by the prescription of other psychotropic medications). This nding is in line with studies showing that therapeutic doses of BZD are not associated with heightened aggressive behavior [27,28], but it is in contrast to other research that reports an association between use of BZD and aggressive behavior [1,23]. Importantly, we also found no association between the dosage of BZD and duration of their use and almost all kinds of punishable behaviors.
The only signi cant result was that use of BZD for longer periods of time might increase the likelihood of engaging in disinhibited, but not directly aggressive behaviors. However, the effect size of this nding was very small: with an increase in the duration of BZD use by one day, detained persons were 1.00 times more likely to exhibit disinhibited, but not directly aggressive behaviors.
The second aim of the study was to investigate whether BZD prescription was associated with using and tra cking illicit or addictive substances during imprisonment. We found that detained persons taking BZD were not more likely to commit offenses involving illicit or addictive substance use or tra cking.
This did not change when we examined the dosage and duration of BZD use, which suggests that taking BZD even in higher dosages and over a longer period of time does not seem to lead to substance-related offenses in the prison setting. This nding has important implications because prescribing BZD in prisons is often avoided on the grounds of their presumed greater abuse potential [19,20]. However, abuse of BZD usually occurs in individuals with a history of substance use disorders; without this history, BZD may be administered safely even in higher dosages and for a relatively long period of time (on average, three months in our sample), with no risk that such use would inevitably lead to other substance abuse [29]. Our ndings lend support to this notion in the prison setting.
Our study has also revealed other important ndings about the use of BZD in the prison setting. The proportion of detained persons who were prescribed BZD (21.3%) is by no means negligible. Moreover, when compared with detained persons who were not prescribed BZD, those using BZD were also prescribed signi cantly more often all other classes of psychotropic agents and medications for general medical conditions, which suggests that they had more mental health and general medical problems. A poorer mental and physical health of these detained persons indicates their greater need for adequate healthcare.
Following the principle of the equality of care, prison populations should bene t from effective and evidence-based treatments that are available in the community. In the context of our study, this means that access to BZD in the prison setting should be subject to the same regulations as in the community [2,22]. The same applies to other psychotropic medications, as well as psychological interventions for mental disorders. It is important to acknowledge that there are very few alternatives to psychotropic medications in the prison system [30] and that treatment of many mental health issues should not only rely on medications such as BZD.

Limitations
This study has a number of limitations. First, it was based on associations and was conducted retrospectively, which precludes us from making inferences about any causal relationship. Second, punishable behaviors recorded by the prison administration were the only indicator of aggressive and disinhibited behavior, and we had no access to any information about punishable behaviors that were concealed or undetected. Future studies should be conducted prospectively and use instruments for assessing irritability, anger, behavioral disinhibition and aggressiveness. Third, our ndings are based on a sample of male detained persons in a Swiss setting and it is uncertain to what extent they can be applied to female detained persons in another country. Fourth, there were no data on psychiatric diagnoses and reasons for prescribing BZD, which might have been helpful to better understand and contextualize the risk of aggressive behavior and disinhibition. Finally, prescribing any medication does not necessarily mean that it will be taken as prescribed, and we have no way of knowing whether detained persons were actually using BZD as prescribed.

Conclusion
Detained persons are a vulnerable population with a high burden of psychiatric and general medical morbidity; they should receive appropriate, timely and evidence-based treatment without institutional barriers to treatment access. Our ndings make a signi cant contribution to the literature in terms of suggesting that prescribing BZD to detained persons is just as safe as prescribing these medications to those who are not detained. More speci cally, we did not nd support for the notions that BZD increase aggressive or disinhibited behavior in detained persons or that they increase the risk of substance abuse in this population. As with other pharmacological agents, BZD should be used carefully and cautiously in the prison setting, along with evidence-based psychological interventions.

Declarations
Ethics approval and consent to participate.Approval for conducting the study was received from the Cantonal Research Ethics Committee of Bern (no. 2016-01539).
Consent for publication. Not applicable.
Availability of data and materials. The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
Competing interest.The authors declare that they have no competing interests.
Authors contributions.SB, VS, IF, AS, AG, RS, and ML made substantial contributions to the study conception and data acquisition. SB and KB performed the statistical analyses. SB and VS drafted the manuscript. All authors made substantial contributions in the interpretation of the data and revised the manuscript critically for important intellectual content. All authors approved the nal version to be published and agreed to be accountable for all aspects of the work related to its accuracy and integrity.