Evaluation of the Efficacy of Propranolol in the Treatment of Patients with Anxiety and Post-traumatic Stress Disorder

Summary

Here, we present a clinical study to investigate how propranolol performs clinically in treating anxiety and post-traumatic stress disorder (PTSD).

Abstract

Patients with anxiety and post-traumatic stress disorder (PTSD) require combined psychological and pharmacological treatment, but evidence on propranolol's efficacy in these conditions remains insufficient.

A retrospective analysis was conducted on 211 eligible patients (after exclusion) with anxiety-related disorders or PTSD (per ICD-11 criteria) admitted to Ganzhou Third People's Hospital from January 2022 to December 2024. Patients were divided into the control group (conventional treatment, n = 105) and the experimental group (propranolol treatment, n = 106). Main outcomes included heart rate (HR), systolic/diastolic blood pressure (SBP/DBP), and Hamilton Anxiety Scale (HAMA) score. Secondary outcomes covered respiratory rate (RR), Beck Depression Inventory-II (BDI-II), Clinical Global Impression (CGI), Post-Traumatic Stress Disorder Checklist-Specific (PCL-S) scores, and adverse reaction incidence.

Baseline characteristics were comparable between groups (P > 0.05). Post-treatment, the experimental group showed significant reductions in HR, SBP, DBP, and RR (all P ≤ 0.003), as well as lower HAMA, BDI-II, and PCL-S scores (all P ≤ 0.004) compared with the control group. CGI score and adverse reaction incidence were also decreased in the experimental group (P = 0.004 and P = 0.037, respectively).

Propranolol effectively relieves anxiety and depression in patients with anxiety and PTSD, reduces adverse reactions, and improves treatment efficacy, providing a scientific basis for clinical medication optimization.

Introduction

Emotions influence cognition and behavior and mediate the different needs of organisms to adapt to their environment¹. Anxiety is characterized by excessive fear and worry-related behavioral disruptions. The manifestations of anxiety include internalizing and externalizing features, which are related to different types of situations and objects². As outlined in the 4th Edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-4), PTSD was regarded as a type of AD. However, since PTSD shows a connection with specific events, PTSD was classified as a trauma stress-related disorder in DSM-5³. Nevertheless, there are still many similar considerations between anxiety and PTSD, including vulnerability, genetics, structural and functional neuroanatomy, involvement of the autonomic nervous system, sleep disruption, and treatment. Moreover, the two also share similarities in phenomenology, including hyperarousal, enhanced startle response, irritability, avoidance, and sleep difficulties. Genetic factors that increase the susceptibility to anxiety-related disorders and PTSD include polymorphisms of the serotonin transporter receptor (SLC6A4), the glucocorticoid receptor binding protein (FKBP5), and the BDNF gene^4,5. Epigenetic modifications of the glucocorticoid receptor can affect the stress response, and chronic stress affects gene alterations, and these, in turn, shape the progression of anxiety and PTSD symptoms. The pathophysiological characteristics of anxiety and PTSD include adrenal, autonomic, structural, functional, and inflammatory features. Patients with PTSD have strong autonomic responses, including increased heart rate (HR) and blood pressure (BP), and decreased HR variability in response to perceived threats. In adults with GAD, it has been reported that the HR during rest is lower and the HR variability is reduced⁶. The mental symptoms are characterized by constant worry and nervousness, and the somatic symptoms are hyperfunction symptoms pertaining to the autonomic nervous system, based on mental symptoms, such as palpitation, chest tightness, and muscular tension tremor. In addition to the above similar factors, exposure to adversity can increase the risk of developing AD and PTSD⁷. Suicidal ideation is common in PTSD and anxiety-related disorders.

At present, effective therapeutic approaches for anxiety-related disorders and PTSD are mainly divided into two categories, namely pharmacotherapy and psychotherapy. These two treatment modalities provide basic regimens for clinical intervention, yet certain limitations remain in practical application. For instance, some medications have a delayed onset of action, a subset of patients exhibit poor response to monotherapy, psychotherapy has limited efficacy in patients with impaired cognitive function, and the dropout rate among PTSD patients is relatively high⁸. Therefore, there is an urgent need to explore more targeted and practical treatment strategies.

Currently, effective treatments for anxiety-related disorders and PTSD include drug therapy and psychotherapy⁹. In recent years, in the field of drug therapy, propranolol has been extensively studied, leading to its new application in psychiatry. As the first successfully developed β-adrenergic receptor blocker, this drug exerts negative chronotropic, inotropic, and dromotropic effects by competitively antagonizing β1 and β2 adrenergic receptors¹⁰. In the early stage, it was mainly used in the treatment of cardiovascular diseases such as angina pectoris, arrhythmia, and hypertension. Its pharmacological effect stems from the competitive antagonism of catecholamines (especially adrenaline and noradrenaline), which reduces sympathetic nerve tone and myocardial oxygen consumption, thereby alleviating the state of excessive load on the cardiovascular system¹¹. In terms of pharmacokinetics, propranolol is mainly metabolized by the hepatic cytochrome P450 system (especially CYP2D6), producing active metabolites such as 4-hydroxypropranolol¹². The application of propranolol has gone beyond the boundaries of the traditional cardiovascular field, demonstrating remarkable multi-target treatment characteristics. A meta-analysis proposed that β-adrenergic receptors figure in memory formation processes, and curbing their activation of β-adrenergic receptors is a new approach for treating psychological disorders caused by maladaptive memories (such as PTSD, GAD)¹³. In addition, propranolol works to dampen emotional arousal, ease stage fright, and mitigate cognitive problems tied to anxiety¹⁴. In a randomized double-blind experiment targeting eight databases conducted by Sereena Pigeon et al., administering propranolol combined with memory reactivation could successfully weaken emotional memories. Compared with the Placebo group, in healthy individuals whose memories were reactivated under propranolol, the physiological responses induced by cues and the declarative memory of emotional materials decreased (P=0.002)¹⁵. In addition, propranolol is also used in other mental diseases. For example, propranolol has been found to effectively reduce aggressive self-harming behavioral patterns shown by those with autism spectrum disorder (ASD) and improve the cognitive processing ability of ASD patients^16,17,18. The core mechanism by which propranolol improves anxiety and PTSD-related symptoms is that it has high lipophilicity, enabling it to pass through the barrier separating blood from brain smoothly and act on the body's central neural system. By blocking the noradrenergic system, it regulates the reconsolidation of emotional memories. Notably, this characteristic not only explains its central hypotensive mechanism but also lays the foundation for its application in the field of neuropsychiatric diseases¹⁴.

This study aims to explore the therapeutic effect of propranolol in patients with AD and PTSD who have similar genetic characteristics, pathophysiology, and anxiety feedback. The comprehensive efficacy analysis is mainly conducted from the patients' basic indicators, such as HR, systolic blood pressure (SBP), diastolic blood pressure (DBP), respiratory rate (RR), scores of commonly used scales for mental state assessment, including the Hamilton Anxiety Scale (HAMA)¹⁹, Beck Depression Inventory-II (BDI-II)²⁰, Posttraumatic Stress Disorder Checklist-Specific (PCL-S)²¹, Clinical Global Impression (CGI)²², and the incidence of adverse reactions^17,18. It is expected that using propranolol to treat patients with AD and PTSD will bring more practical treatment options to the patients and provide theoretical value for promoting the construction of the psychiatric discipline system and diversified drug therapies.

The innovations of this study are mainly reflected in three aspects. First, it achieves precise focus and improved representativeness of the research population. For the first time, it specifically enrolls patients with comorbid AD, anxiety, and PTSD, filling the gap in previous studies²³ that mostly explored the efficacy of propranolol in patients with simple anxiety or PTSD alone, while lacking attention to comorbid populations with cognitive impairment, and thus providing targeted data for clinical medication in special groups. Second, it realizes comprehensive innovation of the efficacy evaluation system by constructing an integrated assessment framework. Compared with previous studies²⁴ that mostly focused on single emotional scale scores, this framework can more comprehensively reflect the impact of interventions on patients' autonomic nervous function, emotional state and overall clinical efficacy, enhancing the reliability of the results and their clinical reference value. Third, it optimizes the adaptability of the intervention duration and monitoring protocol. Based on the particularity of the research population, a short-term 2-week intervention cycle combined with a refined monitoring protocol is set. This not only clarifies the short-term efficacy of propranolol combined with psychotherapy, but also provides new ideas for the design of clinical short-term intervention programs for acute symptoms of anxiety and PTSD. Meanwhile, by accurately distinguishing between drug adverse reactions and symptoms of the disease itself, it offers a referenceable standardized method for safety assessment in subsequent similar studies.

Protocol

This clinical study complied with relevant ethical regulations, such as the Declaration of Helsinki, was reviewed and approved by Ganzhou Third People's Hospital Ethics Committee (ethics approval number: gzsyy2024076), and detailed explanations of the research purpose, procedures, and potential risks were provided to the subjects or their agents, with written informed consent obtained.

General information
This study retrospectively selected 221 patients with AD and PTSD admitted to Ganzhou Third People's Hospital from January 2022 to December 2024 as the research subjects, aiming to evaluate the therapeutic effect of propranolol in the field of psychiatry. The study adopted consecutive enrollment and included both in-hospital admitted cases and externally referred cases. As shown in the experimental design flowchart in Figure 1, 215 cases were included after exclusion, 4 cases were lost to follow-up, and finally, 211 cases were analyzed in total. They were divided into a control group and an experimental group according to the treatment method. There were 105 cases in the control group and 106 cases in the experimental group.

Inclusion criteria
Study eligibility criteria comprised confirmed diagnoses of AD and PTSD per the Clinical Descriptions and Diagnostic Guidelines for Mental, Behavioral and Neurodevelopmental Disorders in ICD-11 (2023 Edition)²⁵, no hypersensitivity to investigational agents, age ≥ 18 years, and complete clinical data plus relevant examinations.

Exclusion criteria
Exclusion criteria included patients with severe heart, liver, or kidney diseases, drug allergies, glaucoma, or who were pregnant; individuals with comorbid mental disorders and a history of alcohol or drug abuse; and subjects who had taken psychiatric medications or antipyretic analgesics within the preceding two weeks^26,27.

Treatment methods
The control group consisted of 52 patients with anxiety disorders (AD) and 53 patients with post-traumatic stress disorder (PTSD). A routine group psychotherapy was administered to these 105 patients to address the shared anxiety symptoms in their emotional profiles.

Grouping method
The grouping was performed using a two-dimensional matching method, with the following specific procedures:

The Generalized Anxiety Disorder 7-item scale (GAD-7) was used to assess the patients' anxiety severity. Scores were categorized into three levels: mild (0-4 points), moderate (5-9 points), and severe (10-21 points).

Patients were divided into groups of 7-10 cases each based on their disease type (AD/PTSD), anxiety severity level, and similar pathogenic factors.

The grouping process was independently completed by two researchers to ensure the objectivity of group allocation.

Treatment protocol
Each session of group psychotherapy was fixed at 1.5 h and divided into two phases, with the specific process as follows:

Phase 1: Disease knowledge lecture (45 min)
A uniformly developed PPT presentation was adopted, and the content strictly adhered to the lecture outline predefined by this study to prevent therapists from arbitrarily adding or deleting content. For patients with anxiety disorders (AD), the lecture focused on "the association between cognitive decline and anxiety" and "how to alleviate anxiety through simple behavioral training (e.g., regular daily routines, memory recall exercises)". For patients with post-traumatic stress disorder (PTSD), the key topics included "the relationship between traumatic memories and anxiety attacks" and "normalized interpretation of stress responses", so as to prevent patients from perceiving their own symptoms as "abnormal" and thus exacerbating their psychological burden.

Phase 2: Group discussion (45 min)
The session was guided by therapists in accordance with predefined questions to ensure consistency in the direction of discussion.

Empathy and acceptance
During the group discussion, therapists created a safe and trusting communication atmosphere through active listening and empathetic feedback, preventing patients from avoiding expression due to symptom-related shame.

Emotional regulation and support
Patients were guided to sort out the associations between anxiety, disease symptoms, and psychosocial factors, helping them recognize the rationality of their own emotional responses. Meanwhile, experience sharing among peers enhanced patients' sense of social support and alleviated loneliness.

Positive reinforcement
Positive affirmation was given to patients who voluntarily shared their experiences and attempted emotional management during the discussion, so as to boost their enthusiasm for engaging in treatment²⁸.

The treatment was administered 4 times per week for 2 consecutive weeks, totaling 8 sessions. All group psychotherapy sessions in this study were co-conducted by psychotherapists who held intermediate or higher-level national psychotherapist qualifications and had more than 5 years of clinical experience, in collaboration with physicians possessing certified qualifications for psychiatric practice. All therapists involved received 2-day standardized training prior to the intervention. The entire course of treatment was carried out in a standardized psychotherapy room, which could accommodate group activities of 7-10 participants and was equipped with basic medical devices such as sphygmomanometers and electrocardiographs to promptly address any physical discomfort that patients might experience during the sessions. After each session, the therapists were required to complete a Group Psychotherapy Session Record Form, documenting in detail the patients' participation levels, emotional responses, and the occurrence of any abnormal conditions.

Propranolol dosage
There were 53 patients with AD and 53 patients with PTSD in the experimental group. For these 106 patients, starting from the routine group psychotherapy used in the control group, propranolol drug treatment was given. Hydrochloride propranolol was used. Patients took it orally 3 times a day, 20 mg each time, with a total of 60 mg/day. It could be taken with meals or on an empty stomach, and the medication was continued for 2 weeks^29,30. According to the Clinical Practice Guidelines for Prevention and Treatment of Anxiety Disorders in China³¹, the conventional dosage range of propranolol for anxiety symptom management is 40-120 mg/day. The dosage of 60 mg/day adopted in this study falls within the low-to-moderate segment of this safe and effective range. This dosage not only blocks central and peripheral β-receptors to inhibit sympathetic nervous system activation, thereby alleviating anxiety-related somatic symptoms such as palpitations, hand tremors, and nervous sweating in patients, but also reduces the risk of adverse reactions associated with excessively high doses.

While giving patients drug treatment, it's equally important to take note of closely observing the patients, determine the patients' breathing conditions and BP changes, observe whether there are adverse reactions such as dry mouth, tachycardia, headache, and insomnia after the patients take the medicine, and take active preventive measures to ensure the patients' life safety.

Observation indicators

Measurement of patients' basic indicators HR, SBP, DBP, and RR
HR is measured using the digital twelve-channel electrocardiograph. SBP and DBP are measured using an electronic BP monitor. RR is measured by auscultation using a general stethoscope. Measurements were taken once on the day prior to medication initiation (baseline period). During the medication course, measurements were performed twice daily: 30 min before the first morning dose and 2 h after the last afternoon dose. An additional measurement was conducted on the second day following the completion of medication to assess the recovery of indicators after drug withdrawal. To eliminate interference from physical activity and emotional fluctuations on the indicators, all patients were required to sit quietly and rest for 15 min in a tranquil, temperature-controlled treatment room before each measurement. During this period, talking, standing up, drinking water, or eating was prohibited to ensure the accuracy and comparability of the measured data.

Scores of mental state scales HAMA, BDI-II, and PCL-S
The HAMA scale is primarily employed to gauge how severe anxiety symptoms are in individuals with neurosis and similar conditions¹⁹. It consists of 14 items and uses a 5-level scoring method from 0 to 4 scores. A total score ≤ 29 may indicate severe anxiety; 21-29 definitely indicates obvious anxiety; 14-21 definitely indicates anxiety; 7-14 may indicate anxiety; if the score is < 7, there is no anxiety.

The BDI-II scale is specifically designed to evaluate the degree of depression and contains 21 items, each of which is related to depressive symptoms²⁰. It employs a 4-point scoring system, with individual items scored from 0 to 3 and the total score spanning 0 to 63. The standard scores are as follows: 0-13: normal range, indicating that there may be no or only mild depressive symptoms; 14-19: grade I depression; 20-28: grade II depression; 29-63: grade III depression. The PCL-S is used to evaluate the severity of an individual's psychological reactions after a specific traumatic event²¹. It consists of a total of 17 items, with a total score ranging from 17 to 85. A higher score indicates a greater likelihood of PTSD. The scoring criteria are as follows:17-37: No obvious symptoms of PTSD; 38-49: Some degree of PTSD symptoms; 50-85: Relatively obvious symptoms of PTSD, and the individual may be diagnosed with PTSD. From the perspective of clinicopathological characteristics, patients with AD and PTSD are often comorbid with depressive symptoms. Studies have confirmed³² that the incidence of comorbid depressive symptoms in patients with anxiety disorders can reach 35%-58%, and the comorbidity rate of depression in patients with PTSD is as high as 40%-65%. The two conditions share close associations in terms of neurobiological mechanisms and clinical symptom manifestations. The use of the BDI-II to assess depressive symptoms in patients can comprehensively reflect the overall impact of intervention measures on patients' emotional symptoms, avoiding the interference of comorbid depression on efficacy evaluation that might be overlooked if only the core symptoms of anxiety/PTSD are focused on.

The first scale assessment was completed on the day prior to the intervention (baseline period) to obtain the baseline symptom levels of the patients. A follow-up measurement was conducted two weeks after the intervention to evaluate the sustainability of the therapeutic effect. Before completing the scale assessment, all patients were required to sit quietly and rest for 15 min in a tranquil, undisturbed evaluation room. During this period, the use of electronic devices, talking, and other activities were prohibited. Only after their emotional and physiological states stabilized were the patients instructed to fill out the scales by uniformly trained evaluators.

Treatment effect CGI scale score
CGI is a standardized tool for evaluating the severity of patients' diseases and treatment effects, and it is divided into three dimensions. This study used the dimension of disease severity (CGI-SI) for evaluation, with a score range of 0-7, and a score of ≥ 4 scores is defined as moderate or more severe severity²².

The first scale assessment was completed on the day prior to the intervention (baseline period) to obtain the baseline symptom levels of the patients. A follow-up measurement was conducted two weeks after the intervention to evaluate the sustainability of the therapeutic effect. Before completing the scale assessment, all patients were required to sit quietly and rest for 15 min in a tranquil, undisturbed evaluation room. During this period, the use of electronic devices, talking, and other activities were prohibited. Only after their emotional and physiological states stabilized were the patients instructed to fill out the scales by uniformly trained evaluators.

Incidence of adverse reactions during treatment
Considering the pharmacological characteristics of propranolol and the similar pathological characteristics of anxiety-related disorders and PTSD, the adverse reactions during treatment include dry mouth, tachycardia, headache, insomnia, etc.^17,18. Adverse reactions in this study were monitored by medical staff who hold practicing qualifications in psychiatry and have received standardized training. Objective indicators, including heart rate and blood pressure, were recorded using a standardized electronic sphygmomanometer and electrocardiograph; an immediate electrocardiogram examination was performed if any abnormalities were detected. Subjective assessments were conducted with reference to the Guidelines for the Prevention and Treatment of Anxiety Disorders in China³¹. Monitoring was carried out twice daily: once in the morning before medication administration and once in the afternoon after medication administration. The onset time, duration, and severity of adverse reactions were recorded in detail throughout the study to ensure comprehensive and accurate identification of adverse reactions and their differentiation from the symptoms of the disease itself. In response to the possible adverse reactions that may occur during propranolol treatment, this study formulated a predefined standardized management protocol, with specific interventions as follows, For patients with mild adverse reactions (e.g., mild xerostomia and dizziness), the dosage of propranolol was not adjusted; only symptomatic care (e.g., supplementary water intake and guidance on slow postural changes) was provided, along with enhanced monitoring of vital signs. For patients with moderate adverse reactions (e.g., persistent headache and a mild decrease in heart rate to 55-60 beats/min), the dosage of propranolol was promptly adjusted to 10 mg per dose, three times a day, with close monitoring of symptom changes and physiological indicators. For patients with severe adverse reactions (e.g., heart rate < 55 beats/min accompanied by dizziness and syncope, or systolic blood pressure < 90 mmHg), propranolol was immediately discontinued, the emergency assessment process was initiated, and symptomatic treatment (e.g., fluid replacement and administration of heart rate-elevating drugs) was given. Transfer to a specialist department for further management was arranged if necessary.

Expected efficacy indicators
The end of the 2-week intervention course was set as the assessment endpoint in this study. The expected efficacy indicators include the following aspects:

Clinical signs: For all patients, anxiety-related somatic symptoms such as tension-induced hand tremors and akathisia were alleviated. For patients with PTSD, avoidance behaviors toward trauma-related topics were reduced, and their participation in group therapy was improved. For patients with AD, mood fluctuations were decreased, and their treatment compliance was enhanced.

Vital signs: Vital signs should be stable within the normal reference range (heart rate: 60-100 beats/min; systolic blood pressure: 90-140 mmHg; diastolic blood pressure: 60-90 mmHg; respiratory rate: 12-20 breaths/min), and show a mild downward trend compared with the baseline values. This trend indicates that propranolol exerts a safe and effective regulatory effect on the sympathetic nervous system.

Abnormal indicators requiring vigilance: If a patient presents with a heart rate < 55 beats/min or systolic blood pressure < 90 mmHg accompanied by dizziness and syncope, or a heart rate > 110 beats/min accompanied by persistent palpitations, medication should be immediately suspended and cardiac function should be evaluated. If a patient's anxiety and insomnia symptoms are aggravated, PTSD patients experience an increased frequency of traumatic flashbacks, or AD patients suffer from a significant short-term decline in cognitive function, psychological treatment strategies should be adjusted and the drug dosage should be re-evaluated. Aggravated adverse reactions such as dry mouth accompanied by dysphagia and persistent headache for more than 48 h without relief should be promptly intervened and documented.

Sample size calculation method
This study is a retrospective clinical controlled trial. The sample size was obtained through the G*Power 3.1.9.7. The number of samples included was divided into a control group and an experimental group according to the treatment method, and was calculated by means of an independent samples t-test based on the primary outcome of anxiety. Referring to previous studies, such as the study by Serge A Steenen et al.²⁵ on the use of propranolol for short-term anxiety after post-traumatic stress reaction, where an effect size of 0.5 was considered to be clinically significant. Considering an α level of 0.05 and a statistical power of 95%, we calculated that a sample size of 42 patients was required for each group. Considering the influence of potential unknown factors, the sample size selected for analysis in this study, the control group comprised 105 patients, while the experimental group included 106 patients. We believe that the sample size of this study can yield reliable conclusions.

Statistical methods
Statistical analysis of the data was performed using SPSS 27.0 software. A normality test (Shapiro-Wilk test) was conducted on the data. For the measurement data, if they conformed to the normal distribution, a paired t-test was used for intragroup comparisons and an independent samples t-test for intergroup comparisons, with the results expressed as mean ± SD. If the measurement data did not conform to the normal distribution, the results were presented as median (interquartile range) [M (Q₁, Q₃)], and Wilcoxon signed-rank test was adopted for intragroup comparisons while Mann-Whitney U test was used for intergroup comparisons. For the enumeration data, they were expressed as n (%), and the chi-square test was applied for intergroup comparisons. All statistical tests were two-tailed, and a value of P < 0.05 was considered statistically significant.

Results

Comparison of baseline data between the two groups
In this retrospective cohort study, statistical analysis was performed on the baseline data characteristics of patients, including age, body mass index (BMI), gender, height, weight, and disease type. No significant differences were observed between the control group and the experimental group (P = 0.793, 0.053, 0.827, 0.275, 0.992, 0.99), indicating comparability. There were no statistical differences in the previous medical histories of pa...

Discussion

Propranolol has a highly selective blocking effect on β receptors and can competitively bind to the receptors, thereby counteracting the β receptor effects of neurotransmitters and adrenergic agonists. It can slow down the HR, reduce cardiac output, and cardiac oxygen consumption. For blood vessels, it can increase peripheral resistance, resulting in a decrease in blood flow to the liver, kidneys, intestines, and coronary arteries, and inhibit renin activity, so it can lower BP. It is also capable of crossing t...

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
Digital twelve-channel electrocardiograph	Shenzhen Mindray Precision Medical Electronics Co., Ltd.	SE-1202
Electronic BP monitor	OMRON	HEM-1026
General stethoscope	3M Company	3m Littmann
Hydrochloride propranolol	Jiangsu Yabang Aipusen Pharmaceutical Co., Ltd.	H32020133