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Cover Focus | September 2022

Challenge Case Report: Tic Disorder in an Adult

Both nonpharmacologic and pharmacologic treatments improve tic frequency and severity., danielle larson, md, clinical presentation.

JB is age 35, right-handed, with a history of generalized anxiety disorder, and presenting to clinic for evaluation and management of unusual movements that began in adolescence. JB also makes brief vocalizations including throat clearing and grunting. The movements and vocalizations have become more frequent and disabling, evolving from rare, mild, and manageable to preventing use of a computer or holding an effective business meeting. There is an anticipatory sensation and urge to perform the movements beforehand followed by relief after completing the movements. JB can suppress these tics temporarily, but after several seconds there is a building urge to perform them.

Medical and Family History

These unusual movements began occurring when JB was age 6 as sudden, brief, jerking movements of the neck and brief shoulder shrugs. In adolescence, JB was diagnosed with a tic disorder by a neurologist and told that the tics would resolve on their own with time; no therapeutics were tried.

JB’s generalized anxiety began in adolescence and is currently poorly controlled owing to life stressors. JB takes 0.5 mg clonazepam tablets, as needed, up to 3 times daily for anxiety; rarely drinks alcohol; and reports being a nonsmoker who uses no other drugs.

Family history is notable for obsessive compulsive disorder (OCD)-like behaviors in JB’s father and anxiety in JB’s brother.

Diagnostic Evaluations

JB’s neurologic exam is remarkable for frequent brief shoulder shrugs, jerky head turns to the right, and throat clearing. Findings of the cranial nerve, motor, sensory, cerebellar, and reflex examinations are unremarkable.

Complete blood chemistry (CBC), comprehensive metabolic panel (CMP), thyroid-stimulating hormone (TSH), and vitamin B 12 levels were all within normal limits. A brain CT was unremarkable. Neuropsychologic testing showed relatively mild impairments in perceptual reasoning with mild inattentiveness and mild retrieval-based difficulty in verbal memory.

Challenge Questions

1. Which of the following features from JB’s history is NOT unique to tic phenomenology?

A. Premonitory urge preceding the movement

B. Temporary suppressibility of the movement

C. Quick, jerky movement

D. Transitory relief after performing the movement

Click here for the answer

C, Quick, jerky movements are NOT unique to tic phenomenology and may be seen in functional neurologic disorders, neuromuscular disorders, seizures, and other neurologic conditions. In contrast to those disorders, however, tics are characterized by premonitory urges, temporary suppressibility, and transitory relief after movements occur. 1

2. Which of the following is NOT required for the diagnosis of classic Tourette syndrome?

A. Onset of tics before age 18

B. Male sex

C. Presence of both motor and phonic tics

D. Persistence of tics beyond the period of 1 year

B, Male sex/gender is NOT required for the diagnosis of classic Tourette syndrome (TS). Although TS is reported to be 3 to 4 times more common in boys than girls, it has also been reported that this is attenuated in adulthood. 2 Diagnostic criteria for TS require the presence of at least 1 motor and 1 phonic tic for at least 1 year with onset before age 18 years. 3

3.Which of the following medications is NOT a recommended pharmacologic treatment for tics?

A. Clonidine

B. Topiramate

C. Levetiracetam

D. Olanzapine

C, Levetiracetam is an antiseizure medication (ASM) that is NOT a recommended pharmacologic treatment for tic disorders. The ASM, topiramate, has shown efficacy in 1 randomized controlled clinical trial. 4 Clonidine and guanfacine are alpha-2-agonists that have been shown superior to placebo for tic reduction in multiple clinical trials and are first-line treatment for tics. 5-7

Tic Disorder in an Adult

Diagnosis and Treatment

JB’s semivoluntary movements, associated with preceding urges, temporary relief, and brief suppressibility, are consistent with tics. Considering tic onset before age 18 years, the presence of multiple motor and phonic tics, tic persistence beyond 1 year, and the lack of any other possible etiology for his symptoms, JB was diagnosed with Tourette syndrome (TS). Because of the moderate severity of the tics and interference with daily life, both pharmacologic and nonpharmacologic treatments were recommended. Guanfacine was prescribed and a referral made for comprehensive behavioral intervention for tics (CBIT)/habit reversal training (HRT) for tics. JB was also referred to psychiatry for further evaluation and management of anxiety that has recently flared and contributed to tic severity.

At a 4-month follow-up visit, JB reported that tic severity and frequency had improved by roughly 50% with the initiation of low-dose guanfacine and completion of 4 of 8 scheduled CBIT/HRT sessions. JB had also established care with a psychiatrist, who has gradually discontinued clonazepam, and recently started working with a psychotherapist for anxiety. In general, JB was happy with the improvement in tics and felt their function at work was improved.

Tics are semivoluntary, purposeless movements that are typically rapid, arrhythmic, and stereotyped. The movements are classically preceded by a premonitory sensation or urge and associated with relief after the tic is performed. 1 Tics are commonly temporarily suppressible, but this is often associated with a building urge to perform the tic.

TS is a neurodevelopmental disorder of unclear etiology characterized by the presence of at least 1 motor and 1 phonic tic with onset before age 18 years that lasts over 1 year, according to diagnostic criteria. 2 TS affects an estimated 0.3% to 1% of the population and is more common in men but occurs in all sexes/genders. 2 Onset of tics is typically between age 4 and 8 years. TS is often familial; first-degree relatives of individuals with tic disorders have a significantly higher risk of TS or other chronic tic disorders. 8,9

In TS, tic frequency and severity tend to wax and wane over the years, with roughly 20% of TS cases persisting into adulthood. 10 Individuals have their own unique set of tics; different tics may develop or abate over the lifespan.

Comorbid attention deficit disorder (40%-60%) and OCD (20%-40%) are strongly associated with TS, occurring at rates more than 10 times higher than in the general population. 11-14 Anxiety (50%-70%) and depression (50%-60%) are frequently present as well. 13

Clinically, tic severity and frequency can be assessed through history taking and examination. Tics can negatively affect an individual’s quality of life by causing social or emotional distress, physical discomfort, or impaired function (in work, driving, sleeping, or other activities of daily living). When tics are causing these impairments, treatment should be initiated.

The initial intervention recommended is CBIT, specifically HRT, which is typically an 8-session treatment with a trained provider based on tic awareness, development of competing response incompatible with tic execution, and relaxation training. 10 Efficacy in reducing tic severity and improving quality of life has been established in randomized control trials (RCTs). 15,16

Pharmacologic therapy should be considered when behavioral therapy is not an option (owing to insurance, limited provider availability, and other barriers to access), has been completed but there is residual tic burden, or tics are severe or need to be addressed quickly. On average, medications reduce tic symptoms by 25% to 50%. 17 There are 3 categories of medications for tics as follows.

Nondopaminergic Agents. The nondopaminergic alpha-2-agonists clonidine and guanfacine are first-line treatments. Clonidine has been used to treat TS for over 30 years with efficacy compared with placebo demonstrated in several RCTs. 5,6 Common side effects include sedation, bradycardia, hypotension, and dry mouth. Guanfacine has a lower risk of sedation and hypotension compared with clonidine and has also been shown to be superior to placebo in RCTs. 5,7 Topiramate, an antiseizure medication with GABAergic properties, has also been shown to effectively reduce tics in 1 clinical RCT. 4

Dopamine Receptor Blockers . As classic dopamine receptor blockers, multiple typical and atypical antipsychotics are approved for tic treatment. Although RCT results support efficacy in tic reduction, these agents are typically reserved for severe or refractory tics owing to undesirable side-effect profiles. Antipsychotics carry the risk of tardive dyskinesia (TD), which can compound the distress and treatment complexity for people with TS.

Dopamine-Modulating Vesicular Monoamine Transporter-2 (VMAT-2) Inhibitors. The VMAT-2 inhibitors offer an alternative to antipsychotics with a better side effect profile and no risk of TD. Although the classic VMAT-2 inhibitor tetrabenazine and newer-generation deutetrabenazine and valbenazine have open-label data showing tic treatment efficacy, RCT results have not corroborated these findings and all are used on an “off-label” basis for tic treatment. 18,19

Importantly, in addition to directly addressing tic severity and frequency with CBIT and/or medications, an individual’s co-morbidities (eg, obsessive-compulsive disorder, attention deficit disorder, anxiety, or depression) should be adequately addressed (with psychiatry referral and pharmacotherapy as needed) to optimize tic improvement.

1. Martino D, Madhusudan N, Zis P, Cavanna AE. An introduction to the clinical phenomenology of Tourette syndrome. Int Rev Neurobiol. 2013;112:1-33.

2. Lichter DG, Finnegan SG. Influence of gender on Tourette syndrome beyond adolescence. Eur Psychiatry . 2015;30(2):334-340.

3. American Psychiatric Association. Neurodevelopmental disorders. In: Diagnostic and Statistical Manual for Mental Disorders. 5th ed. American Psychiatric Publishing; 2013:31-86..

4. Jankovic J, Jimenez-Shahed J, Brown LW. A randomised, double-blind, placebo-controlled study of topiramate in the treatment of Tourette syndrome. J Neurol Neurosurg Psychiatry . 2010;81(1):70-73.

5. Quezada J, Coffman K. Current approaches and new developments in the pharmacological management of Tourette Syndrome. CNS Drugs . 2018;32(1):33-45.

6. Du Y, Li H, Vance A, et al. Randomized double-blind multicentre placebo-controlled clinical trial of the clonidine adhesive patch for the treatment of tic disorders. Aust NZ J Psychiatry . 2008;42(9):807-813.

7. Scahill L, Chappell PB, Kim YS, et al. A placebo controlled study of guanfacine in the treatment of children with tic disorders and attention deficit hyperactivity disorder. Am J Psychiatry. 2001;158(7):1067-1074.

8. Knight T, Steeves T, Day L, Lowerison M, Jette N, Pringsheim T. Prevalence of tic disorders: a systematic review and meta-analysis. Pediatr Neurol . 2012;47(2):77–90.

9. Mataix-Cols, D, Isomura K, Pérez-Vigil A. Familial risks of Tourette syndrome and chronic tic disorders. A population-based cohort study.J AMA Psychiatry . 2015;72(8):787-793.

10. Hassan N, Cavanna AE. The prognosis of Tourette syndrome: implications for clinical practice. Funct Neurol . 2012;27(1):23-27.

11. Leckman JF, Walker DE, Goodman WK, Pauls DL, Cohen DJ. “Just right” perceptions associated with compulsive behavior in Tourette’s syndrome. Am J Psychiatry . 1994;151(5):675-680.

12. Coffey BJ, Biederman J, Smoller JW, et al. Anxiety disorders and tic severity in juveniles with Tourette’s disorder. J Am Acad Child Adolesc Psychiatry . 2000;39(5):562-568.

13. Coffey BJ, Miguel EC, Biederman J, et al. Tourette’s disorder with and without obsessive-compulsive disorder in adults: are they different?. J Nerv Ment Dis . 1998;186(4):201-206.

14. Comings DE, Comings BG. A controlled study of Tourette syndrome. I. Attention-deficit disorder, learning disorders, and school problems. Am J Hum Genet . 1987;41(5):701-741.

15. Van de Griendt JM, Verdellen CW, van Dijk MK, Verbraak MJ. Behavioural treatment of tics: habit reversal and exposure with response prevention. Neurosci Biobehav Rev . 2013;37(6):1172-1177.

16. Piacentini J, Woods DW, Scahill L, et al. Behavior therapy for children with Tourette disorder: a randomized controlled trial. JAMA . 2010;303(19):1929-1937.

17. Roessner V, Schoenefeld K, Buse J, Bender S, Ehrlich S, Münchau A. Pharmacological treatment of tic disorders and Tourette syndrome. Neuropharmacology . 2013;68:143-149.

18. Jankovic J, Glaze DG, Frost JD Jr. Effect of tetrabenazine on tics and sleep of Gilles de la Tourette’s syndrome. Neurology . 1984;34(5):688-692.

19. Jankovic J, Jimenez-Shahed J, Budman C, et al. Deutetrabenazine in tics associated with Tourette syndrome. Tremor Other Hyperkinet Mov (NY) . 2016;6:422

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Case Study Research Method in Psychology

Saul Mcleod, PhD

Editor-in-Chief for Simply Psychology

BSc (Hons) Psychology, MRes, PhD, University of Manchester

Saul Mcleod, PhD., is a qualified psychology teacher with over 18 years of experience in further and higher education. He has been published in peer-reviewed journals, including the Journal of Clinical Psychology.

Learn about our Editorial Process

Olivia Guy-Evans, MSc

Associate Editor for Simply Psychology

BSc (Hons) Psychology, MSc Psychology of Education

Olivia Guy-Evans is a writer and associate editor for Simply Psychology. She has previously worked in healthcare and educational sectors.

On This Page:

Case studies are in-depth investigations of a person, group, event, or community. Typically, data is gathered from various sources using several methods (e.g., observations & interviews).

The case study research method originated in clinical medicine (the case history, i.e., the patient’s personal history). In psychology, case studies are often confined to the study of a particular individual.

The information is mainly biographical and relates to events in the individual’s past (i.e., retrospective), as well as to significant events that are currently occurring in his or her everyday life.

The case study is not a research method, but researchers select methods of data collection and analysis that will generate material suitable for case studies.

Freud (1909a, 1909b) conducted very detailed investigations into the private lives of his patients in an attempt to both understand and help them overcome their illnesses.

This makes it clear that the case study is a method that should only be used by a psychologist, therapist, or psychiatrist, i.e., someone with a professional qualification.

There is an ethical issue of competence. Only someone qualified to diagnose and treat a person can conduct a formal case study relating to atypical (i.e., abnormal) behavior or atypical development.

 Famous Case Studies

• Anna O – One of the most famous case studies, documenting psychoanalyst Josef Breuer’s treatment of “Anna O” (real name Bertha Pappenheim) for hysteria in the late 1800s using early psychoanalytic theory.
• Little Hans – A child psychoanalysis case study published by Sigmund Freud in 1909 analyzing his five-year-old patient Herbert Graf’s house phobia as related to the Oedipus complex.
• Bruce/Brenda – Gender identity case of the boy (Bruce) whose botched circumcision led psychologist John Money to advise gender reassignment and raise him as a girl (Brenda) in the 1960s.
• Genie Wiley – Linguistics/psychological development case of the victim of extreme isolation abuse who was studied in 1970s California for effects of early language deprivation on acquiring speech later in life.
• Phineas Gage – One of the most famous neuropsychology case studies analyzes personality changes in railroad worker Phineas Gage after an 1848 brain injury involving a tamping iron piercing his skull.

Clinical Case Studies

• Studying the effectiveness of psychotherapy approaches with an individual patient
• Assessing and treating mental illnesses like depression, anxiety disorders, PTSD
• Neuropsychological cases investigating brain injuries or disorders

Child Psychology Case Studies

• Studying psychological development from birth through adolescence
• Cases of learning disabilities, autism spectrum disorders, ADHD
• Effects of trauma, abuse, deprivation on development

Types of Case Studies

• Explanatory case studies : Used to explore causation in order to find underlying principles. Helpful for doing qualitative analysis to explain presumed causal links.
• Exploratory case studies : Used to explore situations where an intervention being evaluated has no clear set of outcomes. It helps define questions and hypotheses for future research.
• Descriptive case studies : Describe an intervention or phenomenon and the real-life context in which it occurred. It is helpful for illustrating certain topics within an evaluation.
• Multiple-case studies : Used to explore differences between cases and replicate findings across cases. Helpful for comparing and contrasting specific cases.
• Intrinsic : Used to gain a better understanding of a particular case. Helpful for capturing the complexity of a single case.
• Collective : Used to explore a general phenomenon using multiple case studies. Helpful for jointly studying a group of cases in order to inquire into the phenomenon.

Where Do You Find Data for a Case Study?

There are several places to find data for a case study. The key is to gather data from multiple sources to get a complete picture of the case and corroborate facts or findings through triangulation of evidence. Most of this information is likely qualitative (i.e., verbal description rather than measurement), but the psychologist might also collect numerical data.

1. Primary sources

• Interviews – Interviewing key people related to the case to get their perspectives and insights. The interview is an extremely effective procedure for obtaining information about an individual, and it may be used to collect comments from the person’s friends, parents, employer, workmates, and others who have a good knowledge of the person, as well as to obtain facts from the person him or herself.
• Observations – Observing behaviors, interactions, processes, etc., related to the case as they unfold in real-time.
• Documents & Records – Reviewing private documents, diaries, public records, correspondence, meeting minutes, etc., relevant to the case.

2. Secondary sources

• News/Media – News coverage of events related to the case study.
• Academic articles – Journal articles, dissertations etc. that discuss the case.
• Government reports – Official data and records related to the case context.
• Books/films – Books, documentaries or films discussing the case.

3. Archival records

Searching historical archives, museum collections and databases to find relevant documents, visual/audio records related to the case history and context.

Public archives like newspapers, organizational records, photographic collections could all include potentially relevant pieces of information to shed light on attitudes, cultural perspectives, common practices and historical contexts related to psychology.

4. Organizational records

Organizational records offer the advantage of often having large datasets collected over time that can reveal or confirm psychological insights.

Of course, privacy and ethical concerns regarding confidential data must be navigated carefully.

However, with proper protocols, organizational records can provide invaluable context and empirical depth to qualitative case studies exploring the intersection of psychology and organizations.

• Organizational/industrial psychology research : Organizational records like employee surveys, turnover/retention data, policies, incident reports etc. may provide insight into topics like job satisfaction, workplace culture and dynamics, leadership issues, employee behaviors etc.
• Clinical psychology : Therapists/hospitals may grant access to anonymized medical records to study aspects like assessments, diagnoses, treatment plans etc. This could shed light on clinical practices.
• School psychology : Studies could utilize anonymized student records like test scores, grades, disciplinary issues, and counseling referrals to study child development, learning barriers, effectiveness of support programs, and more.

How do I Write a Case Study in Psychology?

Follow specified case study guidelines provided by a journal or your psychology tutor. General components of clinical case studies include: background, symptoms, assessments, diagnosis, treatment, and outcomes. Interpreting the information means the researcher decides what to include or leave out. A good case study should always clarify which information is the factual description and which is an inference or the researcher’s opinion.

1. Introduction

• Provide background on the case context and why it is of interest, presenting background information like demographics, relevant history, and presenting problem.
• Compare briefly to similar published cases if applicable. Clearly state the focus/importance of the case.

2. Case Presentation

• Describe the presenting problem in detail, including symptoms, duration,and impact on daily life.
• Include client demographics like age and gender, information about social relationships, and mental health history.
• Describe all physical, emotional, and/or sensory symptoms reported by the client.
• Use patient quotes to describe the initial complaint verbatim. Follow with full-sentence summaries of relevant history details gathered, including key components that led to a working diagnosis.
• Summarize clinical exam results, namely orthopedic/neurological tests, imaging, lab tests, etc. Note actual results rather than subjective conclusions. Provide images if clearly reproducible/anonymized.
• Clearly state the working diagnosis or clinical impression before transitioning to management.

3. Management and Outcome

• Indicate the total duration of care and number of treatments given over what timeframe. Use specific names/descriptions for any therapies/interventions applied.
• Present the results of the intervention,including any quantitative or qualitative data collected.
• For outcomes, utilize visual analog scales for pain, medication usage logs, etc., if possible. Include patient self-reports of improvement/worsening of symptoms. Note the reason for discharge/end of care.

4. Discussion

• Analyze the case, exploring contributing factors, limitations of the study, and connections to existing research.
• Analyze the effectiveness of the intervention,considering factors like participant adherence, limitations of the study, and potential alternative explanations for the results.
• Identify any questions raised in the case analysis and relate insights to established theories and current research if applicable. Avoid definitive claims about physiological explanations.
• Offer clinical implications, and suggest future research directions.

5. Additional Items

• Thank specific assistants for writing support only. No patient acknowledgments.
• References should directly support any key claims or quotes included.
• Use tables/figures/images only if substantially informative. Include permissions and legends/explanatory notes.
• Provides detailed (rich qualitative) information.
• Provides insight for further research.
• Permitting investigation of otherwise impractical (or unethical) situations.

Case studies allow a researcher to investigate a topic in far more detail than might be possible if they were trying to deal with a large number of research participants (nomothetic approach) with the aim of ‘averaging’.

Because of their in-depth, multi-sided approach, case studies often shed light on aspects of human thinking and behavior that would be unethical or impractical to study in other ways.

Research that only looks into the measurable aspects of human behavior is not likely to give us insights into the subjective dimension of experience, which is important to psychoanalytic and humanistic psychologists.

Case studies are often used in exploratory research. They can help us generate new ideas (that might be tested by other methods). They are an important way of illustrating theories and can help show how different aspects of a person’s life are related to each other.

The method is, therefore, important for psychologists who adopt a holistic point of view (i.e., humanistic psychologists ).

Limitations

• Lacking scientific rigor and providing little basis for generalization of results to the wider population.
• Researchers’ own subjective feelings may influence the case study (researcher bias).
• Difficult to replicate.
• Time-consuming and expensive.
• The volume of data, together with the time restrictions in place, impacted the depth of analysis that was possible within the available resources.

Because a case study deals with only one person/event/group, we can never be sure if the case study investigated is representative of the wider body of “similar” instances. This means the conclusions drawn from a particular case may not be transferable to other settings.

Because case studies are based on the analysis of qualitative (i.e., descriptive) data , a lot depends on the psychologist’s interpretation of the information she has acquired.

This means that there is a lot of scope for Anna O , and it could be that the subjective opinions of the psychologist intrude in the assessment of what the data means.

For example, Freud has been criticized for producing case studies in which the information was sometimes distorted to fit particular behavioral theories (e.g., Little Hans ).

This is also true of Money’s interpretation of the Bruce/Brenda case study (Diamond, 1997) when he ignored evidence that went against his theory.

Breuer, J., & Freud, S. (1895).  Studies on hysteria . Standard Edition 2: London.

Curtiss, S. (1981). Genie: The case of a modern wild child .

Diamond, M., & Sigmundson, K. (1997). Sex Reassignment at Birth: Long-term Review and Clinical Implications. Archives of Pediatrics & Adolescent Medicine , 151(3), 298-304

Freud, S. (1909a). Analysis of a phobia of a five year old boy. In The Pelican Freud Library (1977), Vol 8, Case Histories 1, pages 169-306

Freud, S. (1909b). Bemerkungen über einen Fall von Zwangsneurose (Der “Rattenmann”). Jb. psychoanal. psychopathol. Forsch ., I, p. 357-421; GW, VII, p. 379-463; Notes upon a case of obsessional neurosis, SE , 10: 151-318.

Harlow J. M. (1848). Passage of an iron rod through the head.  Boston Medical and Surgical Journal, 39 , 389–393.

Harlow, J. M. (1868).  Recovery from the Passage of an Iron Bar through the Head .  Publications of the Massachusetts Medical Society. 2  (3), 327-347.

Money, J., & Ehrhardt, A. A. (1972).  Man & Woman, Boy & Girl : The Differentiation and Dimorphism of Gender Identity from Conception to Maturity. Baltimore, Maryland: Johns Hopkins University Press.

Money, J., & Tucker, P. (1975). Sexual signatures: On being a man or a woman.

Further Information

• Case Study Approach
• Case Study Method
• Enhancing the Quality of Case Studies in Health Services Research
• “We do things together” A case study of “couplehood” in dementia
• Using mixed methods for evaluating an integrative approach to cancer care: a case study

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Case studies in a musculoskeletal out-patients setting

CHAPTER EIGHT Case studies in a musculoskeletal out-patients setting Adrian Schoo, Nick Taylor, Ken Niere, with a contribution from James Selfe Case study 1: Jaw Pain 217 Case study 2: Headache 218 Case study 3: Neck Pain – Case One 221 Case study 4: Neck Pain – Case Two 224 Case study 5: Thoracic Pain 226 Case study 6: Low Back Pain – Case One 228 Case study 7: Low Back Pain – Case Two 231 Case study 8: Shoulder Pain 234 Case study 9: Elbow Pain 237 Case study 10: Hand Weakness and Pain 239 Case study 11: Groin Pain 241 Case study 12: Hip and Thigh Pain 244 Case study 13: Medial Knee Pain 247 Case study 14: Anterior Knee Pain 249 Case study 15: Calf Pain 252 Case study 16: Achilles Pain 254 Case study 17: Ankle Sprain 256 Case study 18: Fibromyalgia 258 Introduction Musculoskeletal problems are very common, and can be encountered in hospital emergency departments, orthopaedics, and out-patient physiotherapy ( Carter & Rizzo 2007 ). It is not uncommon for in-patients who are admitted for another problem to be referred and treated in the ward or in the out-patient department for a musculoskeletal problem. The prevalence of specific conditions can vary between the different groups in the community. For example, sporting injuries are more likely to occur in the younger groups, whereas degenerative conditions such as osteoarthritis are more likely to occur as people progress in years. Musculoskeletal problems can result in pain and functional limitations (disability), and represent a major burden to the society due to associated health care costs and loss of productivity ( National Health Priority Action Council 2004 ). Musculoskeletal conditions, including arthritis, cause more disability than any other medical condition and affect one-third of all people with disability. Since part of the chronic disease burden is attributed to risk factors such as physical inactivity ( Bauman 2004 ) people with musculoskeletal conditions are often referred to physiotherapy out-patients for management of their conditions. As in other areas of physiotherapy practice, musculoskeletal assessment and treatment requires a systematic clinical reasoning approach ( Edwards et al 2004 ). The clinical reasoning approach used in this chapter considers: (i) differential diagnoses based on assessment and clinical presentation; (ii) intervention based on the best evidence available; (iii) constant evaluation of therapy outcomes; (iv) adjustment of intervention programme in line with diagnosis and stage of progress; and (v) referring to or working together with other disciplines to exclude and or address confounding problems. In assessing and treating common musculoskeletal conditions and measuring progress it is important to use outcome measures that are valid and reliable, and that consideration must be given to impairments of body structure and function as well as activity limitation and participation restriction, such as ability to return to work. The World Health Organization’s International Classification of Functioning, Disability and Health (ICF) provides a useful framework for physiotherapists in out-patients to assess patient functioning ( Jette 2006 ). Referral to or working with other disciplines may involve tests such as X-rays or dynamic ultrasound scans, or the provision of orthotics to improve biomechanics. In addition to specific techniques, treatment may require education, ergonomic advice and the instruction of a home exercise programme to improve outcomes on function and pain. There is an emerging and increasing body of research on the effectiveness of physiotherapy that provides the clinician in out-patients with an evidence base for their practice ( Herbert et al 2001 ). For example, there is high level evidence that therapeutic exercise can benefit clients across broad areas of physiotherapy practice ( Morris & Schoo 2004 , Taylor et al 2007 ). In prescribing exercises it can be important to know whether the exercise programme is performed correctly and adhered to by the client. Conditions such as back problems or tendinopathies may be negatively affected by incorrect activity performance. Additional problems that can affect health outcomes are incorrect belief systems and mental health problems. For instance, people with osteoarthritis may think that movement harms the joint, but by not moving they put themselves at risk of developing problems associated with physical inactivity (e.g. increased morbidity and mortality due to cardiovascular problems or falls) ( Philbin et al 1996 ). Also, people with chronic pain may be depressed and are, therefore, less likely to be interested in performing exercises, and may benefit from counselling (e.g. motivational interviewing). Screening patients for problems such as fear-avoidance behaviour and anxiety ( Andrews & Slade 2001 ), asking about past and current exercise performance, motivating them if needed (Friedrich et al 1998) and demonstrating the prescribed exercises can assist in determining the likelihood of correct and consistent programme performance (Friedrich et al 1996b, Schneiders et al 1998 ). We have selected common musculoskeletal conditions that are likely to be encountered in hospital out-patient departments. The different cases relate to younger and older people, females as well as males. A multitude of physical tests and outcome measures have been included together with clinical reasoning and evidence-based treatment options. CASE STUDY 1 Jaw pain Subjective examination Subject 34-year-old female office worker HPC Left sided headaches off and on for 3/12 Increasing pain of the left temporomandibular joint (TMJ) last 2/12 Pain at night, at rest, and when opening the mouth or chewing PMH Appendectomy Stress at work Aggravating factors Biting a big apple Chewing hard or tough food Easing factors Rest is better than chewing, although remains painful Drinking fluid Ice Night Wakes up because of pain Grinds teeth when asleep (according to partner) Daily pattern Constant pain that worsens during and directly after opening the mouth or chewing General health Using prescribed sedatives due stress at work. No other problems reported Attitude/expectations Given the symptoms she expects that it may take some time for them to settle Pain and dysfunction scores VAS current pain at rest = 3 VAS usual level of pain during chewing in the last week = 7 VAS worst level of pain during opening the mouth in the last week = 9 Objective examination Palpation Skin temperature (T sk ) normal Left TMJ painful on palpation TMJ movement and clicking can be felt when placing the index finger in the auditory canal and opening the mouth No signs of TMJ dislocation when comparing left with right Muscle length External pterygoid muscle feels tight and painful on opening of the mouth (palpation through the mouth) Functional testing, including ROM and strength Opening of the mouth is limited. It can accommodate two fingers only. Normally, the span is large enough to accommodate three fingers ( Hoppenfield 1986 ) Asymmetrical mandibular motion with severe swinging to the left when opening the mouth Questions 1. What is your provisional diagnosis? 2. What signs and symptoms lead you to this diagnosis? 3. How will you address these in your treatment plan? 4. What kind of common and less common problems need to be excluded? 5. How likely is it that the patient’s stress and teeth grinding contribute to the current complaint? 6. How will the expectations of the patient influence your treatment? 7. Is the patient likely to benefit from referral to other health professionals? CASE STUDY 2 Headache Subjective examination Subject 29-year-old male working on Help Desk in Information and Computer Technology HPC Gradual onset of headaches and cervical pain about 3/52 ago Cannot recall precipitating incident Headaches becoming more frequent (now daily) and lasting longer (up to 3 hours) Has deep ache (non-throbbing) radiating from the back of the occiput to the right frontal region. Also complaining of stiffness like pain in the right side of the cervical spine. Neck pain and headache seem related (see Figure 8.1 ) FIGURE 8.1 Body chart – Case Study 2 . PMH Car accident 10 years ago which led to cervical pain for about 3/52. No problems since apart from an occasional stiff neck Aggravating factors Prolonged work at the computer (if more than 2 hours brings on headache) Reversing the car reproduces slight cervical stiffness Easing factors Analgesia dulls the headache Night Sleep undisturbed Daily pattern Seems to depend on how long he has spent at the computer General health In good health, no weight loss No complaints of dizziness, no nausea or vomiting Assessed as being depressed, has been taking antidepressants over the last 3/12 Investigations No X-rays or other investigations at this stage Attitude/expectations At the moment headache is not affecting him a lot but wanted to get it checked out in case it is something serious Keen not to miss any work Intends to continue normal recreation of sail boarding this weekend Pain and dysfunction scores Neck Disability Index: 14% Disability VAS level of pain when headache is most severe (after working at the computer for 2 hours) = 6 Physical examination Observation Forward head posture with a slouched sitting posture Palpation Hypo-mobility of upper cervical joints on the right, with reproduction of local cervical pain Increased muscle tone in right upper trapezius and right levator scapulae Movements Active movements Right cervical rotation equals 60° with slight stiffness in neck Left cervical rotation equals 75–80° Limited cervical retraction, feels stiff Muscle function Decreased strength and endurance of the deep cervical neck flexors as determined by the cranio-cervical flexion test ( Jull et al 1999 ) Neurodynamic testing Upper limb neurodynamic/tension test (base test): In 90° shoulder abduction and full external rotation, right elbow extension lacks 40° while left lacks 30°. Reproducing local neck pain, which is eased with cervical lateral flexion towards the right Neurological tests (tests of nerve conduction) Not assessed Questions 1. What is your provisional diagnosis? 2. What signs and symptoms led to your provisional diagnosis? 3. How will you address these in your treatment plan? 4. What kind of common and less common problems need to be excluded? 5. How relevant are work details for this patient? 6. How will the expectations of the patient influence your treatment? 7. Is the patient likely to benefit from referral to other health professionals? CASE STUDY 3 Neck pain – case one Subjective examination Subject 32-year-old male accountant HPC Prolonged sitting (all day) at a conference 3/52 previously Noticed onset of left lower cervical and interscapular pain at the end of the day On waking the next morning pain had spread to the posterior aspect of the arm and forearm as far as the middle three fingers (see Figure 8.2 ) FIGURE 8.2 Body chart – Case Study 3 . Seen by doctor 1/52 ago. Doctor ordered plain X-rays including oblique views that did not show any abnormality Has not improved at all since onset of symptoms Medical history High cholesterol, overweight, sedentary lifestyle Minor neck complaints that usually settled within 2 or 3 days Aggravating factors Sitting for more than 10 minutes increases neck pain. More than 30 minutes increases arm pain Looking up or to the left increases neck and arm pain Lifting briefcase with left hand aggravates neck and interscapular pain Easing factors Neck pain relieved by lying supine Arm pain relieved by lying supine with left arm above head Night Can sleep 2–3 hours at a time before being woken by increased neck and interscapular pain Changing position helps to decrease the pain Daily pattern Increased symptoms with increased amounts of sitting, particularly if using computer Medication Was prescribed non-steroidal anti-inflammatory medication (Meloxicam) which helps take the edge off the neck pain Attitude/expectations Wants to know what the problem is, particularly as the X-rays did not show any abnormality Feels that something might be ‘out’ in his neck. If it could be ‘put back in’ the symptoms should resolve Physical examination Observation Sits with forward head posture Cervical active movements in sitting Extension reproduces pain in the neck and left arm at 30°. Movement occurs mainly in the upper and mid-cervical regions. Very little movement in the lower cervical or upper thoracic areas Right rotation produces a stretching in the left cervical region at 75° Left rotation reproduces left neck and interscapular pain at 40° Palpation Increased tone and tenderness noted in the left paraspinal muscles (cervical and upper thoracic) and left scalene muscles Local pain and left arm pain reproduced by postero-anterior (PA) pressures over the spinous processes of C6 and C7 and over the C6 and C7 articular pillars on the left Generalized stiffness noted with PA pressures in the mid and upper thoracic regions Segmental neurological examination Absent left triceps jerk Weakness in left triceps (25% of right side) Decreased sensation to light touch over the tip of the left middle finger Questions 1. What is the most likely source of the patient’s arm pain? 2. What is the most likely source of the patient’s neck and interscapular pain? 3. What are other possible symptoms sources? 4. Are there reasons to be cautious in administering physiotherapy treatment? 5. What would an appropriate initial physiotherapy treatment involve? 6. What would a longer-term management programme include? 7. What is the likely prognosis? 8. Is referral to other health professionals warranted? CASE STUDY 4 Neck pain – case two Subjective examination Subject 23-year-old female personal assistant HPC Rear end motor car accident 2/7 ago Immediate onset of cervical pain and stiffness (left and right). Both pain and stiffness have been increasing. Pain is now constant Vague headache started today (see Figure 8.3 ) FIGURE 8.3 Body chart – Case Study 4 . Seen by doctor yesterday who organised an X-ray (no abnormality detected) and referred patient to physiotherapy PMH Left knee reconstruction 3 years ago with good return of function since No past history of neck complaints Aggravating factors Turning head to either side, especially if movement is quick Travelling in car – took 20 minutes to settle after 30-minute car trip Easing factors Supine with head supported on one pillow Felt a bit easier under hot shower Night Wakes often due to discomfort Sleeps on 3 pillows Difficulty turning in bed due to pain Daily pattern Constant pain that gradually worsens during the day General health Taking non-prescription analgesics every 4 hours on advice of doctor. No other medications Not seeing the doctor for any other health problems Attitude/expectations Anxious about prognosis Worried about how much work she will have to miss as she only started in her current position 3/12 ago Pain and dysfunction scores VAS current pain at rest = 5 VAS level of pain after 30 minute car trip = 8.5 Physical examination Observation Walking slowly and all movements are guarded Removes jacket slowly and with great care Neck in slight protracted posture Palpation Generalized tenderness to light palpation of cervical spine (central, left and right) Increased muscle spasm left and right paraspinal muscles Further detailed palpation not possible because therapist wary of exacerbating symptoms Active movements Left rotation equals 30° before pain started increasing Right rotation equals 35° before pain started increasing Attempt to retract cervical spine caused increased pain No other movements tested today Questions 1. What is your provisional diagnosis? 2. Which of the signs and symptoms will you place on your priority list? 3. How will you address these in your treatment plan? 4. What kind of common and less common problems need to be excluded? 5. How relevant are work details for this patient? 6. How will the expectations of the patient influence your treatment? 7. Is the patient likely to benefit from referral to other health professionals? CASE STUDY 5 Thoracic pain Subjective examination Subject 60-year-old male lawyer Presents with bilateral lower thoracic pain with radiation of symptoms anteriorly to the lower sternal area (see Figure 8.4 ) FIGURE 8.4 Body chart – Case Study 5 . Had a similar problem 5 years previously that settled with physiotherapy which resolved after three sessions of passive mobilisation directed to the thoracic spine HPC Noticed onset of symptoms 4/52 previously after lifting pots while gardening. Pain initially felt in sternal area, then onset of thoracic pain over the course of the day Pain initially intermittent, now constant at a level of VAS 2/10 at best and VAS 7/10 at worst Medical history Noticed 5 kg of weight loss in previous 4/52 that could not be explained by other factors Had noticed intermittent, generalised, mild (VAS 1–2/10), aches and pains in trunk, arms and legs over the previous 3/12 that had worsened slightly over the previous 4/52 Aggravating factors Prolonged sitting for greater than 20 minutes at work would increase posterior and anterior chest pains to VAS 6/10 Easing factors Standing and walking for 10 minutes decreases all symptoms to VAS 2/10 Night Wakes 3–4 times each night with increased symptoms in thoracic and sternal areas. Has to get out of bed and walk around to ease pain. Tends to notice generalised aches and pains associated with increased sweating at night Daily pattern Dependent on amount of sitting during the day. More thoracic and sternal pain at end of day when sitting a lot Medication Nil Attitude/expectations Expects that physiotherapy will ease symptoms as they did for a past episode of similar pain Physical examination Observation Increased thoracic kyphosis noted while sitting. Able to actively correct sitting posture, although this increases thoracic pain slightly Thoracic active movements in sitting Extension is restricted by about 50% and reproduces posterior thoracic pain with overpressures localised to the mid/lower thoracic spine Thoracic rotation feels stiff but no pain reproduced Flexion is normal in range and reproduces a stretching feeling in the mid thoracic area Palpation Generalised stiffness noted on midline and unilateral postero-anterior (PA) pressures from T2–T10 Posterior thoracic and anterior pain reproduced with midline PA pressures over T7–T8. These pains settled quickly once the pressure was released Palpation of the ribs, inferior part of the sternum and upper part of rectus abdominis did not reveal any increased tenderness Questions 1. What are your hypotheses regarding the likely source of the thoracic and sternal pains? 2. What would an appropriate initial physiotherapy treatment involve? 3. Are there examination findings that would make you suspect a non-musculoskeletal source of the symptoms? 4. What are red flags? 5. Is referral to other health professionals warranted? CASE STUDY 6 Low back pain – case one Subjective examination Subject 44-year-old male bank manager HPC 4/7 ago bent to reach into boot of car and felt slight backache. Thought it would settle so played golf anyway. Next morning severe low back pain with aching pain radiating down the back of the right leg to just below the knee. Has no pins and needles or numbness (see Figure 8.5 ) FIGURE 8.5 Body chart – Case Study 6 . PMH Has had four or five episodes of low back pain over the last 8 years, usually settles quickly in 2 or 3 days Has not required treatment with previous episodes Aggravating factors Finds it difficult to put shoes and socks on in the morning After driving to work (about 40 minutes) found leg pain had worsened Can only sit for about 15 to 20 minutes at a time at work Has noticed that sneezing increased back and leg pain Easing factors Lying on back eventually relieves the leg pain Standing and walking seem to help a little Night Pain gradually eases after initial discomfort Is waking at night but finds can get back to sleep quite quickly when changes position Daily pattern Back stiff and aches getting out of bed first thing in the morning but eases after shower Back pain is worse by the end of the day, and leg pain is more constant by the end of the day General health Taking non-steroidal anti-inflammatories (NSAIDs) with slight improvement At recent annual review doctor advised to increase physical activity to reduce weight (BMI 26.4) and adjust diet (cholesterol 6.4). Otherwise fit and well Attitude/expectations Very keen not to miss club Stableford golf competition this weekend (in 3/7) Intending to cope with work as best he can. Very busy at work so reluctant to take time off Pain and dysfunction scores Oswestry Disability Score: 36% Disability VAS level of pain after 40 minute car trip: back = 8, leg = 6 Physical examination Observation Slight left-sided contralateral list (when observed from behind in standing shoulders are to the left relative to the hips) Changes position regularly when in sitting position Palpation Increased tone, right erector spinae in the lumbar region Central postero-anterior pressures over the lumbar spine reproduced back pain (but not leg pain) at L4 and L5 Unilateral pressures were painful on the right at L4 and L5 Movements Active movements Lumbar flexion in standing limited (2 cm below the knee) Lumbar extension in standing markedly limited Left and right rotation (assessed in sitting) both more than 60° Attempt to correct contralateral list led to increased back pain Repeated active movements Flexion in standing repeated 10 times led to increased back pain and increase of leg pain Extension in standing repeated 15 times abolished leg pain, and increased range – back pain remained Repeated correction of contralateral list (side gliding to the right) led to reduced central back pain and slightly increased range Neurodynamic tests Straight leg raise: right = 70° left = 70° Slump test not evaluated Neurological tests (tests of nerve conduction) Muscle strength in myotomes L3 to S1, left = right Sensation in dermatomes L2 to S1, left = right Reflexes (patella tendon and Achilles), brisk left = right Questions 1. What is your provisional diagnosis? 2. What is the likely source of the right leg pain? 3. Which of the signs and symptoms will you place on your priority list? 4. How will you address these in your treatment plan? 5. What kind of common and less common problems need to be excluded? 6. How relevant are work details for this patient? 7. How will the expectations of the patient influence your treatment? 8. Is the patient likely to benefit from referral to other health professionals? CASE STUDY 7 Low back pain – case two Subjective examination Subject 49-year-female assembly worker at automotive manufacturer HPC Complaining of increasing back pain over the last 14/12. Back pain is in the central low back region and radiates into both gluteal regions – no leg pain (see Figure 8.6 ). Has been off work for the last 6/12 with no improvement in pain FIGURE 8.6 Body chart – Case Study 7 . Injured back when installing car upholstery 14/12 ago. Initially had 3/7 off work and experienced some slow improvement over the first 3/12 Has had manipulative physiotherapy involving manipulation, mobilisation and traction with no benefit. Also tried chiropractic without benefit PMH 15-year history of intermittent low back pain usually no more than a few days off work Cholecystectomy 6 years ago Aggravating factors Prolonged walking or standing (more than 15 minutes) increases ache Prolonged sitting (more than 15 minutes) increases ache Unable to do weekly shopping or housework as these activities aggravate the ache Easing factors Lying down but only for about 30 minutes, as gets stiff when lying in one position for too long Night Finds it difficult to get comfortable, wakes when turning Not getting good-quality sleep any more Daily pattern Gradually worse by the end of the day General health Has gained weight over the last 14/12 (about 6 kg) Assessed as being depressed, has been taking antidepressants over the last 3/12 Investigations X-ray shows mild bilateral degeneration of the L4–5 facets CT scan shows a minor disc bulge at L4–5 and L5–S1 with no nerve root involvement Attitude/expectations Has reduced activity level to avoid aggravating back Believes that if she can find the right practitioner then they will fix her Very concerned with the CT scan report and the diagnosis of disc pathology Has been more short-tempered with family and friends since her back problem began Her spouse has been very supportive and has willingly taken over tasks such as housework and shopping Pain and dysfunction scores Oswestry Disability Score: 72% Disability VAS level of pain after 15 minutes of standing or sitting = 7.5 Physical examination Observation Exhibits pain behaviours including grimacing, and placing hand on back Changes position regularly when sitting and standing Walking pattern is slow and guarded Palpation Central palpation of the lumbar spine at L1, L2, L3, L4 and L5 painful Unilateral pressures are painful left and right at L1, L2, L3, L4 and L5 Movements Active movements Lumbar flexion in standing limited (2 cm above the knee) Lumbar extension in standing moderately limited (estimated half of expected range) Left and right rotation (assessed in sitting) both about 40° Neural mobility tests Straight leg raise on right = 50° left = 50° Able to fully extend knee in upright sitting Slump test not evaluated Neurological tests (tests of nerve conduction) • Normal no abnormality detected Questions 1. What is your provisional diagnosis? 2. How do you interpret the X-ray and CT scan reports? 3. Which of the signs and symptoms will you place on your priority list? 4. How will you address these in your treatment plan? 5. What kind of common and less common problems need to be excluded? 6. How relevant are work details for this patient? 7. What are yellow flags and how are they relevant for this patient? 8. Is the patient likely to benefit from referral to other health professionals? CASE STUDY 8 Shoulder pain Subjective examination Subject 47-year-old female factory worker Right arm dominant HPC Right shoulder pain which started 1/52 ago when dragging a heavy item onto the conveyor belt. Routinely she has to pull, lift, and reach overhead PMH Low back pain episodes since work-related lifting injury Asthma and frequent coughing Aggravating factors At work: Overhead work, lifting and carrying boxes In transit: Driving car, riding a bike with wide handlebars. At home: Preparing meals, working at the computer, knitting Easing factors Rest Avoiding overhead work or holding elbows out when lifting or carrying items Night Wakes frequently because of pain, particularly when sleeping on the painful shoulder Daily pattern Constant nagging pain that worsens during activities as mentioned above (see aggravating factors ) General health Asthma attacks. Smokes. Using bronchodilatators as needed Attitude/expectations Is afraid that she may need to look for another job due to experiencing increasing shoulder problems at work Wants better duties within the factory as some of her colleagues have managed to do Pain and dysfunction scores VAS current pain at rest = 3 VAS usual level of pain during aggravating activity in the last week = 7 VAS worst level of pain in the last week = 9 Shoulder Pain and Disability Index (SPADI): Pain score = 60%, Disability score = 45%, Total score = 50.8% ( Roach et al 1991 ) Objective examination Standing with arms relaxed Shoulders protracted and depressed (right > left) Right shoulder abducted and elbow flexed Hyper kyphosis Shortness of breath with upper chest breathing Palpation Skin temperature (T sk ) normal Tenderness of subscapularis, supraspinatus and serratus posterior superior with palpable trigger points Painful insertion of subscapularis and supraspinatus on the humerus Palpable click on shoulder abduction Muscle length and strength Tightness of the subscapularis, pectoralis minor Weakness of rhomboids, supraspinatus Functional and other testing, including ROM Painful arc when abducting arm (90–115° abduction) with audible click (VAS rises to 6 during this impingement) Hawkins and Kennedy impingement test (compressing the subacromial tissues by internal rotation in 90° shoulder flexion) was positive ( Ginn 2003 ) and VAS rises to 8 Apprehension test for shoulder stability and SLAP lesion tests were negative, indicating integrity of joint capsule, labrum and ligaments ( Brukner et al 2001e , Ginn 2003 , Hoppenfield 1986 ) Shoulder elevation reduced by 10° with early scapular movement when comparing with left shoulder (VAS rises to 5) Pain on resistance against external rotation and abduction (VAS rises to 8) Reduced internal rotation and adduction strength when pushing palm of the hand on the table when sitting at the table (VAS rises to 7) Difficulty placing right hand behind back. Positive Gerbers’ test (resisting against hand when patient is pushing hand away from the spine (VAS rises to 8) Questions 1. What is your provisional diagnosis? 2. What signs and symptoms lead you to this diagnosis? 3. Describe the mechanism that can leads to this condition. 4. How will you address these signs and symptoms in your treatment plan? 5. What kind of common and less common problems need to be excluded? 6. Can patient’s asthma and hyper kyphosis contribute to the shoulder complaint? 7. How will the expectation of the patient influence your treatment? 8. Is it possible that outcome measures do not reflect the severity of pain and disability experienced by the patient? 9. Is the patient likely to benefit from referral to other health professionals? CASE STUDY 9 Elbow pain Subjective examination Subject 39-year-old male carpenter Right hand dominant HPC Right lateral elbow pain off and on for at least 5/12. Insidious onset Worsened 4/52 ago when his nail gun broke down and he was forced to use a hammer all day Severe pain and reduced strength, particularly when using his arm during activities such as gripping, holding and lifting. Pain radiates into forearm No history of locking PMH Fractured ribs 3 years ago due to fall at work. Landed on his right side, and elbow was pushed into the ribs. No elbow symptoms until 5/12 ago Never experienced any symptoms of the cervical or thoracic spine Minor injuries such as an ankle sprain, mainly due to sport Aggravating factors Firm gripping (e.g. pliers) Hammering Screw driving Using a jackhammer Driving (car has no power steering) Closing a tap Knocking the elbow Easing factors Rest Ice Night Constant ache. Lying on elbow or pulling up the blanket makes it worse Daily pattern Constant pain that worsens during and directly after activity General health No other health problems reported. Not using any medication or receiving any other medical care Attitude/expectations Is disappointed that his elbow problem hasn’t improved over time as his other injuries did Experiencing increasing problems at work. Is afraid that he will lose his job One of his colleagues experienced major improvement after physiotherapy treatment and he hopes that it will help him too Expects that it may take some time since he wants to stay at work Pain and dysfunction scores VAS current pain at rest = 4 VAS usual level of pain during activity in the last week = 8 VAS worst level of pain in the last week = 9–10 Upper Extremity Functional Index (UEFI) 35/80 ( Stanford et al 2001 ) Objective examination Arm at rest while standing Elbow flexed (right > left) Wrist flexed (right > left) Forearm supinated (right > left) Palpation Skin temperature (T sk ) normal Lateral epicondyle extremely painful with some palpable swelling Tenderness extensor carpi radialis brevis and longus Thickening in extensor carpi radialis brevis (ECRB) Difficult to palpate for tenderness of capitellum radii due to surrounding tissue swelling and pain Muscle length ECRB – tight (flexion and ulnar deviation of the wrist, pronation of the forearm, and slight extension of elbow) Extensor carpi radialis longus – tight (flexion and ulnar deviation of the wrist, pronation of the forearm, and complete extension of elbow) Functional testing, including ROM and strength Elbow extension showed pain in at end of ROM (VAS rises to 6) Forearm pronation/supination showed full ROM (VAS rises to 5) Reduced grip strength (VAS rises from 4 to 9 during firm gripping) Difficulty opening pushing door handle and opening door (VAS rises to 7) Difficulty lifting an object with palm of hand facing down (VAS rises to 8) Resistance against dorsiflexion in a dorsiflexed position of the wrist, with fist closed, caused severe pain on the lateral side of the elbow Questions 1. What is your provisional diagnosis? 2. What signs and symptoms lead you to this diagnosis? 3. Describe the mechanism that can lead to the condition 4. What will you include in your treatment plan? 5. What kind of common and less common problems need to be excluded? 6. How likely does the patient’s previous fall contribute to the current complaint? 7. How will the expectations of the patient influence your treatment? 8. Is the patient likely to benefit from referral to other health professionals? CASE STUDY 10 Hand weakness and pain Subjective examination Subject 56-year-old woman who works part-time as a kindergarten assistant Right hand dominant HPC Pain, numbness and tingling noticed in right hand (particularly in the thumb, index and middle fingers) over the last 6/52, especially at night. Insidious onset Has started to have difficulty using right hand for gripping and it is starting to affect work as a kindergarten assistant and tennis Feels it is getting worse, because pain is now extending up the forearm. Is now waking her during the night PMH Diagnosed with non-insulin-dependent diabetes 5 years ago, currently well controlled with diet and exercise (walks for 45 minutes three times a week and plays social tennis twice a week) Knee arthroscopy with partial left medial menisectomy 12 years ago after tennis injury, recovered well Aggravating factors Gripping (tennis racquet after 1 set, a feeling of weakness) Opening jars Packing up play equipment at kindergarten Sleeping Easing factors Gets a little relief from changing position and shaking out wrist Aspirin (started aspirin 2/52 ago on advice of GP), may have helped a little Night Now waking every night (once only) with right wrist pain and numbness Daily pattern Symptoms are dependent on activity. Finds it is painful at end of shift at the kindergarten and after tennis. Otherwise not troubling too much during the day Attitude/expectations Enjoys her regular exercise (especially tennis) so is keen to get the problem fixed She has friends who had surgery for something that sounded similar so is not sure why she was referred to physiotherapy or how it might help Pain and dysfunction scores VAS current pain at rest = 1.5 VAS worst level of pain in the last week = 7 Levine symptom severity scale = 1.9/5.0 Levine functional status scale = 1.4/5.0 Physical examination Observation No abnormality detected No wasting of right thenar eminence Palpation Slight reduction to light touch on the palmar surface of the right thumb and 1st and 2nd finger Movement (right side) Wrist flexion = 60°, no pain Wrist extension = 55°, no pain Wrist supination = 90° from mid-prone, no pain Wrist pronation = 90° from mid-prone, no pain Finger IP flexion OK, no pain Finger MCP flexion OK, no pain Thumb flexion, abduction and opposition OK, no pain Functional testing, including ROM and strength Grip strength assessed on Jamar dynamometer (right = 27 kg with VAS = 3, left = 35 kg) Phalen’s test (sustained bilateral wrist flexion) reproduced numbness on palmar surface of index and middle after 45 seconds Upper limb tension test with a median nerve bias: reproduced right hand symptoms which eased on release of shoulder depression ( Butler 2000 ) Questions 1. What is your provisional diagnosis? 2. What are the anatomical relationships that explain your provisional diagnosis and the patient’s symptoms and signs? 3. Explain the significance of the night symptoms and the positive Phalen’s sign. 4. Are there other assessment techniques that could be used to confirm the provisional diagnosis? 5. Find out what items the Levine symptom severity and functional status scales assesses ( Levine et al 1993 ) and then discuss how this patient rates. 6. Which of the symptoms and signs will you place on your priority list? 7. How will you address these in your physiotherapy treatment plan? 8. Are there other problems that could be contributing to the symptoms? 9. The patient has some friends who had surgery for something similar. What is the role of surgery for this condition? CASE STUDY 11 Groin pain Subjective examination Subject 17-year-old male student Playing in high-level senior soccer team with training three times a week in addition to a match on the weekend Plays as midfielder Right foot dominant HPC About 4/12 ago noticed slight stiffness in groin the morning after a strenuous match. Insidious onset Gradually got worse until about 2/12 ago could not train or play without right-sided groin pain. Performance was also waning with a loss of power and acceleration On advice of team trainer rested from all training and playing for 6/52, but on resumption of training 2/52 ago groin pain returned immediately. Seen by GP who ordered X-rays and a bone scan, and referred him to physiotherapy PMH Well-controlled asthma. Uses one puff of a preventer daily (Flixitide). Rarely needs to use reliever (Ventolin) Episode of Osgood–Schlatters syndrome when 14 years old after joining soccer development squad. Resolved after 1 year through modification of activity Otherwise well and not seeing the doctor for any other condition Aggravating factors Running, especially when sprinting and when cutting (changing direction) Kicking, especially when taking a corner No pain on sneezing or coughing Easing factors Avoidance of aggravating activities Night Sleep unaffected Daily pattern Symptoms are dependent on activity. Now affecting whenever tries to run or kick a ball Notices in morning, takes 10 to 15 minutes to ease Attitude/expectations Concerned that the problem appears to be getting worse. Had thought it would just go away Receives payment for playing in soccer team which he had planned to continue to help support his studies at university Pain and dysfunction scores VAS current pain at rest = 0 VAS worst level of pain in the last week = 9 (kicking across from a corner) VAS worst level of pain in the last week = 8 (when attempting to sprint) Physical examination Observation In standing, no obvious wasting or pelvic asymmetry With walking, observed excessive pelvic tilting (obliquity) in the frontal plane Palpation Tender to palpation at tendon attaching to right medial inferior pubic ramus Trigger point tenderness to muscle belly distal to medial inferior pubic ramus Tender at right side of pubic symphysis Movement Right hip flexion = 130°, no pain = left Right hip extension = 25°, no pain = left Right hip abduction = 45°, pain (VAS = 3), left = 55° Right hip internal/external rotation = left Functional testing Squeeze test (patient supine with hip flexed 45°, examiner places fist between patient knees, and asks patient to bilaterally adduct) reproduced right groin pain (VAS = 4) Resisted straight-leg right hip adduction reproduced right groin pain (VAS = 4) Right hip quadrant (passive hip flexion, adduction and internal rotation) only very slight pain, similar to discomfort when tested on the left side Thomas test (slight restriction on right compared to left with only slight reproduction of pain (VAS = 0.5) when hip flexion resisted) Abdominal muscle testing: 1. global muscles, only slight pain (VAS = 1) on resisted abdominal flexion 2. stabilising muscles, assessed in supine with a pressure cuff biofeedback unit placed in the small of the back. He could increase the pressure in the cuff from 40 to 43 mmHg for 3 seconds 4 times before unwanted activity from global muscles was observed Standing on one leg (Trendelenburg test), only slight drop of pelvis observed, within normal limits (<10°) Investigations (completed 1/52 ago) X-ray: no abnormality detected Bone scan: indicated some increased uptake in the right inferior pubic region Questions 1. What is your provisional diagnosis? 2. What are the key findings from your examination that led to your provisional diagnosis? 3. What other common causes of groin pain did you consider in making your diagnosis? 4. What are some less common causes of groin pain that you need to consider when examining this patient? Briefly explain why these are considered unlikely at this stage. 5. What is Osgood–Schlatter’s disease and what is its relevance to the current condition? 6. What are the significance of the bone scan findings and the assessment of the abdominal stabilising muscles, and do these findings tie in with the other assessment findings? 7. Which of the symptoms and signs will you place on your priority list? 8. How will you address these in your physiotherapy treatment plan? CASE STUDY 12 Hip and thigh pain Subjective examination Subject 38-year-old female Right leg dominant HPC Right lateral hip and thigh pain that can radiate to knee Started approximately 1/12 ago Woke up with pain after a long shopping day PMH Overweight (BMI ≥27) Neck pain and headaches Aggravating factors Walking Sleeping on right side Sleeping on a hard mattress Easing factors Rest and ice Night Wakes up frequently, particularly when lying on right side, or on left side with right hip in adduction and knee resting on the mattress Daily pattern Pain during and after prolonged standing and walking General health Overweight. No other problems reported. Not using any medication Attitude/expectations Is not sure whether treatment will provide immediate relief, but hopes that at least she will be able to sleep better. Between pain experienced at night and her youngest child waking up and demanding attention she does not get much sleep and feels fatigued Pain and dysfunction scores VAS current pain at rest before activity = 2 VAS usual level of pain when waking up at night = 8 VAS usual level of pain during and after activity in the last week = 7 VAS worst level of pain in the last week = 9 Lower Extremity Functional Scale 48/80 ( Binkley et al 1999 ) Objective examination Standing Visibly overweight Wide hips, but knees are touching each other Valgus position of knees and ankles Pronated feet with reasonable longitudinal arches Palpation Although skin temperature (T sk ) around hip and along the thigh appeared normal, that of the posterior aspect of the trochanter may have been a little elevated Tenderness of the iliotibial tract and the bony posterior aspect of the greater trochanter, with a boggy feeling around the location of the bursa ( Hoppenfield 1986 )

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Fecal Microbiota Transplantation (FMT) as an Adjunctive Therapy for Depression—Case Report

Jessica p. k. doll.

1 Department of Psychiatry (UPK), University of Basel, Basel, Switzerland

Jorge F. Vázquez-Castellanos

2 Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven-University of Leuven, Leuven, Belgium

Anna-Chiara Schaub

Nina schweinfurth, cedric kettelhack, else schneider, gulnara yamanbaeva, laura mählmann, serge brand.

3 Center for Affective, Stress- and Sleep Disorders (ZASS), Psychiatric Clinics (UPK), University of Basel, Basel, Switzerland

4 Sleep Disorders Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran

5 Substance Abuse Prevention Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran

6 Division of Sport Science and Psychosocial Health, Department of Sport, Exercise, and Health, University of Basel, Basel, Switzerland

7 Department of Psychiatry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

Christoph Beglinger

8 Department of Research, St. Clara Hospital, Basel, Switzerland

Stefan Borgwardt

9 Department of Psychiatry and Psychotherapy, University of Lübeck, Lübeck, Germany

Jeroen Raes

André schmidt, undine e. lang, associated data.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Depression is a debilitating disorder, and at least one third of patients do not respond to therapy. Associations between gut microbiota and depression have been observed in recent years, opening novel treatment avenues. Here, we present the first two patients with major depressive disorder ever treated with fecal microbiota transplantation as add-on therapy. Both improved their depressive symptoms 4 weeks after the transplantation. Effects lasted up to 8 weeks in one patient. Gastrointestinal symptoms, constipation in particular, were reflected in microbiome changes and improved in one patient. This report suggests further FMT studies in depression could be worth pursuing and adds to awareness as well as safety assurance, both crucial in determining the potential of FMT in depression treatment.

Introduction

Major depressive disorder (MDD) is an illness affecting more than 264 million people worldwide ( 1 ) and influencing functioning and quality of life (QoL) ( 2 ). Despite advancements in the development of therapeutics, current treatments have not reached optimal efficacy and approximately one third of patients do not respond to treatment after two or more trials of antidepressant medication ( 3 , 4 ). Therefore, the identification of new treatment options is crucial.

Recently, interest has been drawn toward the importance of the biochemical signaling between the gastrointestinal (GI) and the central nervous system, also known as the microbiome-gut-brain axis (MGBA) ( 5 – 9 ). Several studies have linked the gut microbiome to depression ( 6 , 8 – 11 ). The gut microbiota composition appears to be altered in depressed people ( 12 – 15 ), presenting predominance of potentially harmful bacterial groups and/or reduction in beneficial bacterial groups ( 12 ). Such dysbiosis could be related to depressive symptoms ( 16 , 17 ), as the MGBA is a bi-directional pathway, which involves multiple communication modalities, including metabolites, the immune system or the vagus nerve ( 8 , 10 , 18 , 19 ). Together, these studies feed the hypothesis that modification of the gut microbiome could decrease MDD symptoms. There are various ways to manipulate the gut microbiome, such as administration of prebiotics ( 20 – 22 ), probiotics ( 21 , 22 ), postbiotics ( 22 ), or fecal microbiome transplantation (FMT) ( 23 ). Preclinical evidence showed that adult germ-free rodents receiving fecal samples from MDD-patients showed increased depressive-like behavior compared to controls ( 17 , 23 ). Therefore, transplanting healthy fecal microbiome to MDD-patients could potentially ameliorate depressive symptoms. The intention of FMT is to introduce a beneficial microbial gut community by transferring intestinal microbiota from a healthy donor to a patient.

FMT has proven to be an effective treatment for recurrent Clostridium difficile infection ( rCDI ) ( 24 , 25 ). To our best knowledge, in MDD only one case treated with FMT has been reported so far ( 26 ).

Therefore, we initiated a randomized controlled trial (RCT), testing the efficacy of oral frozen FMT-capsules as adjuvant therapy in patients with moderate/severe MDD at the University Psychiatric Clinics Basel (UPK). While our RCT was running, the Food and Drug Administration released a safety alert regarding FMT (see Supplementary Methods for details) and we decided to cease the study for safety reasons after including a total of four patients. In the present article, we report clinical and safety results from two cases that had already received the active product.

Case Descriptions

Both patients were women and between 50 and 60 years old ( Table 1 ). Before starting the intervention, both received treatment as usual (TAU), which included pharmacological treatment, psychotherapy and additional medical-therapeutical treatments ( Figure 1 and Supplementary Tables 1, 2 . Changes in their treatment took place based on medical indication and patients' preferences.

Sociodemographic information.

Timeline with relevant timepoints from the episode of study and care.

Patient 1 had a diagnosis of MDD and chronic constipation. According to the patient, her first depressive episode started in adolescence, with a suicide attempt later in life. She was diagnosed with MDD in 2006 and had been hospitalized twice in her life. Depression is common in her family, with two male second-degree relatives having suffered from it, one deceased by suicide. At the time of baseline assessment, the patient had been in therapy as an inpatient for almost 3 months and treated for depression and constipation with persevering symptoms (see Supplementary Table 1 ).

Patient 2 had a diagnosis of MDD. She was diagnosed with depression in 1980 and has been hospitalized twice since then. A family history of depression is unknown. After more than 2 months of inpatient treatment, the patient's symptoms persevered. She was medicated with antidepressants and benzodiazepines ( Supplementary Table 2 ). At time of FMT intervention, the patient was suffering from negative emotions and GI symptoms, such as flatulence and constipation. For a more detailed description of the patients (see Supplementary Case Description ).

Diagnostic Assessment and Study Design

The RCT was approved by the local ethics committee (Ethikkommission Nordwest- und Zentralschweiz) and was conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonization Tripartite Guideline on Good Clinical Practice. Eligible patients were informed about the study and provided written informed consent. The study was registered at ClinicalTrials.gov prior to study start (NCT03281004). MDD-patients were recruited from the UPK (Switzerland). At baseline, we assessed depressive symptoms [Hamilton Depression Rating Scale; HAMD ( 27 ) and Beck Depression Inventory-II; BDI II ( 28 )], GI-symptoms [Gastrointestinal Rating Scale; GSRS ( 29 )] and collected anthropometric and demographic data. Then the intake of oral frozen FMT-capsules followed. After the treatment, participants were observed and assessed on a weekly basis over a period of 4 weeks. After 4 weeks, post-intervention measurements were conducted. Additionally, an 8-week follow-up was performed. Stool samples were collected at baseline and 4 weeks after the intervention. For one of the patients, stool samples were available 8 weeks after the intervention ( Supplementary Material ).

Intervention

Patients were administered 30 oral frozen FMT-capsules within 90 min under the observation of a physician. Each active 30-capsule-dose consisted of 8.25 g donor stool, originating from a single donor, which was a different donor for each patient. For a detailed description of the methods (see Supplementary Methods ).

Both patients adhered to the intervention. They tolerated the oral frozen FMT-capsules well and did not report any serious adverse events (SAEs).

Depressive Symptoms

For patient 1, symptoms of depression improved, indicated by a decreased HAMD-score from 21 points at baseline to nine points 4 weeks post-intervention. At 8-week follow-up, the HAMD-score increased to 19 points ( Figure 2A ). For patient 2, the HAMD-score decreased from 31 to 10 points after 4 weeks and increased by two points after 8 weeks ( Figure 2A ). Thus, the FMT intervention resulted in a 4-week change score of 12 and 21 HAMD-points for patient 1 and 2, respectively, and an 8-week change score of 2 and 19 points, respectively ( Figure 2B ). As the present results come from two cases and do not allow for statistical comparison, we mapped our HAMD change scores together with meta-analysis results from Kirsch et al. ( 30 ) ( Supplementary Figures 1 , 2 ); methods and results can be found in the Supplementary Material . Additionally, we explored the depressive symptoms from two patients, who had received placebo. Both placebo-patients tolerated the placebo-capsules well. HAMD-scores from both placebo-patients only improved within the first 2 weeks after placebo-intake and increased back to baseline scores, which is visible in Supplementary Figures 3A,B (placebo 1: baseline 16, post-intervention 16, follow-up 9; placebo 2: baseline 22, post-intervention 22, follow-up not available).

(A) HAMD-scores for patient 1 and 2 over time, including cut-offs for depressive symptom severity. (B) Change scores of HAMD rating for both patients at 4-weeks compared to baseline and 8-weeks compared to baseline. A higher (and positive) change score indicates improvement of depressive symptoms as the change score was calculated by subtracting the score at post-intervention from the score at baseline (e.g., baseline score: 21, post-intervention score: 9, equals 21–9 = 12). (C) GSRS-scores for both patients over time; without cut-off for GI-symptom severity as different clusters of symptoms are defined by the GSRS (e.g., constipation) and classification of severity would be only possible for each symptom, not for the overall score. (D) GSRS change scores for both patients at 4-weeks compared to baseline and 8-weeks compared to baseline. (E) BDI-II-scores for both patients over time. (F) BDI-II change scores for both patients at 4-weeks compared to baseline and 8-weeks compared to baseline.

The BDI-II-scores dropped for both FMT-patients 4 weeks after FMT; from 50 to 31 points for patient 1 and from 24 to 12 points for patient 2, which results in change scores of 19 and 12, respectively. At 8-week follow-up, patient 1 reported a BDI-II-score of 34 and patient 2 a score of 9, resulting in change scores from baseline to follow-up of 16 and 15, respectively ( Figures 2E,F ).

Gastrointestinal Symptoms

Gastrointestinal symptoms improved in both patients ( Figure 2C ). Patient 1 benefitted by 56 points after 4 weeks, which worsened by only three points after 8 weeks. At baseline, she suffered from stomach pains, sickness, bloating, burping, and constipation. All symptoms improved over time. Patient 2 reported only a slight improvement of three points 4-week post-FMT and continued reporting constipation and bloating. The patient slightly improved by three more points at 8-week follow-up ( Figures 2C,D ).

Microbiome Composition and Diversity

In both patients, moisture decreased over time [ Supplementary Figure 6A ; Mixed-effects model (MEM) ANOVA p adjusted < 0.05]. Our patients showed lower moisture levels than the ones reported in a healthy population ( 31 ) (Wilcoxon test: W = 50, p = 0.025, Supplementary Figure 7 ). The bacterial load reflected in the cell counts was constant among the three time points for both patients (MEM ANOVA p adjuste d = 1). Diversity analysis was done to measure the taxonomic evenness (Pielou index), the richness (the number of observed species) and the diversity (inversed Simpson and Shannon indices) after FMT. Both patients showed an increase in the Pielou index after FMT, suggesting an evolution toward a more even distribution of species ( Figure 3A ). The species richness was generally reduced upon intervention ( Figure 3B ) and sustained until week eight in patient 1 ( Figure 3B ). We found that patient 1 showed increased inversed Simpson and Shannon diversity ( Figures 3C,D ), whereas patient 2 showed decreased diversity ( Figures 3C,D ).

Patients' microbiome diversity. Mixed-effects models (MEM) of the genus level (A) Pielou evenness, (B) observed species, (C) inverse simpson, and (D) Shannon index, the alpha diversity estimators were modeled into a discrete manner and represent its results as boxplot and into a continuous way, representing the MEM slope into line-plots. The gray area into the continuous MEM represents the 95% confidence level. Patient 1 is displayed in purple, patient 2 in orange. (E) Mixed-effects models (MEM) of the ASV after the FMT intervention. The columns remarked in blue indicates the increase in the abundance of the ASV of patient 1, patient 2, and when the increase is congruent between both. Similarly, the columns remarked in blue indicates the decrease of the ASV in time. The blue scale represents the MEM positive coefficient; in red, the negative. The ASV was set as a putative biomarker if both the continuous and discrete mixed-effect-model time coefficients were significant (ANOVA < 0.05).

The FMT intervention revealed a different effect on the bacterial composition of the two patients. Patient 1 maintained the Ruminococcus enterotype over all time points; while patient 2 switched from the Ruminococcus to the Bacteroides-2-enterotype 4 weeks post-intervention ( Supplementary Figure 8 ), indicating a dysbiotic microbial composition previously linked to fast transit and inflammation ( 31 , 32 ). The switch in the bacterial composition was also associated with an increase of the fecal calprotectin levels, which was higher than the ones reported in healthy subjects ( Supplementary Figure 9A ) ( 31 ). However, the bacterial load increased in patient 2 4 weeks post-intervention; the cell counts increased to a level between the 75 and 95 quantile ( Supplementary Figure 9B ) ( 31 ).

The FMT intervention displayed different effects on the taxa abundance between the patients ( Figure 3E ). Patient 1 showed an increase of 13 amplicon sequence variants (ASV) of the genera Alistipes, Oscillibacter, Coprococcus, Clostridium IV , and the families Ruminococcaceae and Lachnospiraceae, the order Clostridiales, and the Firmicutes phylum ( Figure 3E ). Contrary, nine ASV from the genera Victivallis, Alistipes, Roseburia, Prevotella, Ruminococcus, Blautia , and Faecalibacterium and two ASV of the family Lachnospiraceae decreased after FMT ( Figure 3E ). Patient 2 showed an increase of ASV of the Ruminococcaceae family, including Ruminococcus E , and one ASV of the species Flavonifractor plautii ( Figure 3E ), which has been reported to be increased in MDD-patients ( 16 ). Patient 2 showed a decrease of five ASV of the genera Ruminococcus, Alistipes, Bifidobacterium, Oscillibacter , and the family Lachnospiraceae ( Figure 3E ). Further results are documented in the Supplementary Results .

Four weeks after the intake of oral frozen FMT-capsules, depressive symptoms improved in both patients, objectively graded from severe/moderate to mild depression ( 33 ); this is in line with previous results implicating that FMT reduced depressive symptoms in patients with irritable bowel syndrome (IBS) 4 weeks after treatment ( 34 ). Intriguingly, in the study by Kurokawa et al. ( 34 ), the clinical improvement after FMT was accompanied by increased gut bacteria diversity and decreased GI-symptoms. The relationship between IBS and depression seems to be bi-directional ( 34 , 35 ). Both of our patients were not formally diagnosed with IBS, but experienced GI-symptoms at baseline. While patient 1 was able to defecate regularly even 8 weeks after FMT, patient 2 was initially relieved, but after 4 weeks, again afflicted by constipation.

At baseline, both subjects showed a Ruminoccus enterotype bacterial composition and low fecal moisture, a proxy of slow transit time, and congruent with the prevalence of constipation in mood disorders ( 36 – 38 ). Patient 1 increased in diversity and maintained the Ruminococcus enterotype, indicating a better microbial response to FMT. However, the improvement of constipation in patient 1 is not reflected by the enterotype, since Ruminococcus is associated with slow transit time ( 36 , 37 ).

Compared to patient 2, patient 1 showed a higher abundance of short-chain fatty acid (SCFA) producers such as Butyrivibrio and Faecalibacterium that, along with Dialister , seem to be depleted in depressed people ( 16 ). Additionally, patient 1 showed an increase of species related to other healthy commensal species from the genera Methanobrevibacter and Sporobacter . Such species are related to low transit time and a healthy microbial establishment indicating the good recovery of the microbial community after oral frozen FMT-capsules. Moreover, patient 1 showed an increase and decrease of different ASV of the Alistipes genera after FMT. It is reasonable to assume that different Alistipes species may have different roles in host health; it has been reported that the decrease in Alistipes exerts an immunoregulatory effect and contributes to the decrease in SCFA which are suggested to have anti-depressant effects ( 39 , 40 ). Simultaneously, Alistipes are increased in depressed subjects ( 41 ).

Patient 2 still experienced constipation after the oral frozen FMT-capsules. It has been reported that prolonged constipation leads to a dysbiotic microbial configuration ( 42 , 43 ); indeed, patient 2 showed increased fecal calprotectin and switched to the Bacteroides-2-enterotype. Although until now this enterotype has mostly been linked to fast transit, constipated Bacteroides-2-individuals do exist (Raes, unpublished results). This patient's bacterial community showed an increase of species of the Flavonifractor genus, which is related to depression ( 16 , 31 , 44 ), and an increase of species of the Streptococcus genus, which is associated with high calprotectin and pro-inflammatory conditions ( 31 ). We assume that prolonged constipation in depressed people may have compromised the effectiveness of the oral frozen FMT-capsules by preventing the engraftment of the healthy microbial commensal species. A previous case report of FMT, as mono-treatment for depression and introduced via colonoscopy, reported a MDD-patient who also suffered from constipation ( 26 ). Interestingly, 4 days after FMT, the patient's GI- and depressive symptoms improved and persevered until 6 months after FMT ( 26 ).

The positive depression outcome did not persevere for both of our patients. Objective rating of the first patient's depressive condition, who improved GI conditions, indicated moderate depression at 8-week follow-up. Contrary, patient 2, who did not improve greatly on GI conditions, remained within the range of mild depression with a tendency to increase depressive symptoms. A study recently reported significant improvement of QoL and fatigue in IBS-patients 3 months after receiving FMT ( 45 ), which implicates a long-lasting positive effect of FMT compared to our results. They also found dose-dependent effects and that improvement in QoL and fatigue was not entirely in line with improvement of GI symptoms. FMT results on depressive and GI symptoms are conflicting, and RCTs investigating FMT in depressed patients are lacking. While some studies found improvement in depressive symptoms and QoL after FMT ( 34 , 45 ), there is also evidence of QoL and depressive symptoms not being affected by FMT ( 46 ).

One important factor for such mixed results is the general heterogeneity of illness presentation in MDD and IBS populations. As FMT success might depend on the recipient's microbial composition before FMT or on the microbial resemblance of the donor and the recipient, identifying subgroups of depressed patients might be crucial ( 47 ). Another reason could be the differing methodology between studies, such as choosing one (super)donor ( 45 ) or several donors ( 46 ), the FMT administration (e.g., oral capsule or colonoscopy) ( 48 , 49 ), or the formulation (e.g., frozen or fresh) ( 24 , 50 ). Other arising questions regard the optimal dose and durability of FMT ( 45 ). Barbara and Ianiro ( 50 ) discuss such issues of FMT methodology.

Notably, although the small participant number precludes statistical group comparison, the HAMD-scores of the two FMT and the two placebo-patients present interesting descriptive results. We would expect an improvement in depressive symptoms over time as the patients received TAU. Nonetheless, the two placebo participants presented only a 2-week improvement after placebo-capsule intake, which then relapsed to baseline scores. This might be attributed to the placebo effect, especially as one of the placebo participants thought she had received the active product. The other placebo patient reported increased depressive symptoms, which even restrained her from coming to the post-intervention assessment. Combined with the results from the FMT-patients, these results indicate that frozen oral FMT-capsules as add-on therapy might have the potential to improve depressive symptoms.

Critically, the report of cases suffering from SAEs after FMT raises the importance of extensive donor screening and cautious selection of FMT-patients ( 50 ). To overcome these issues, more large-scale controlled clinical studies are needed, investigating gut microbiota modulation in depression, gaining knowledge of its underlying mechanisms, neuroactive potential and beneficial, and harmful microbes and eventually, reconstituting microbes in the laboratory. This would make safety control, retraceability, and substantial FMT production possible ( 50 ). The resulting clinical trials could greatly improve our knowledge and eventually lead to the translation of controlled and specific FMT to clinical practice, and finally, improve depressed people's wellbeing.

Limitations

The current study reports some limitations, starting with the limited sample size. Second, both patients also had comorbidities, such as obesity and constipation, which both might be confounding factors as overweight and constipation seem to be associated with altered gut microbiota composition ( 51 , 52 ). They received FMT additionally to TAU which makes attribution of effects solely to FMT impossible; the outcome could be influenced by other pathologies or be the result of FMT and antidepressants working in synergy as antidepressants may influence the gut microbiota ( 53 ). Additionally, our patients were constipated at baseline, which might be due to medication as some of the medication might modify the transit time ( Supplementary Table 4 ). Third, we did not include any information about the patients' diets. However, diet has been found to be associated with depression ( 54 ) and is one of the most significant modulators of gut microbial community ( 55 ). A fourth limitation is the comparably low amount of donor stool (8.25 g). As the dose may play a crucial role in the effects, future research should also include dose-finding strategies. Further, although a previous study revealed that oral FMT-capsules are non-inferior to colonoscopy in efficacy in CDI -patients ( 25 ), the most efficient delivery mode in patients with depression needs to be established.

Lastly, the microbial resemblance of the donor and recipient may play an important role. As we do not have information on the donors' microbial composition, such comparison was impossible in this report. Future studies should include information on the donors' microbiome and compare it to the recipients' microbiome to identify subgroups for better treatment options.

Patients' Perspectives

Both patients were positive toward the intervention and had a feeling that they had received the active product. They felt better regarding their depressive symptoms, which is visible by the subjective measurement with the BDI-II ( Figures 2E,F ). In 2021 we contacted the patients via telephone, which was ~2.5 and 1.5 years after the intervention for patient 1 and 2, respectively. At that time, both were going on in their daily lives. One participant emphasized that one of her major treatment milestones was FMT.

Data Availability Statement

Ethics statement.

The studies involving human participants were reviewed and approved by Ethikkommission Nordwest- und Zentralschweiz. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

Author Contributions

AS: had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis and study supervision. LM, CB, SBo, AS, and UL: study concept and design. JD, JV-C, ACS, NS, CK, ES, GY, JR, and AS: acquisition, analysis, or interpretation of data. JD, JV-C, and AS: drafting the manuscript. All authors: critical revision of the manuscript for important intellectual content. JD and JV-C: statistical analysis. SBo, AS, and UL: obtained funding. LM, SBr, SBo, JR, AS, and UL: administrative, technical, or material support. All authors contributed to the article and approved the submitted version.

This work was supported by the Gertrud Thalmann-Fonds (SBo, UL), Seerave Foundation (UL), Kämpf-Bötschi Stiftung (UL), and Research Fund Junior Researchers of the University of Basel (Appln 3MS1041, AS). JV-C was supported by the postdoctoral fellowships fromthe Research Fund–Flanders (FWO 1236321N). The Raes lab was supported by VIB, KU Leuven, and the Rega Foundation.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Acknowledgments

We thank Jan Klaproth for information gathering and support in preparing the present case report.

Supplementary Material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fpsyt.2022.815422/full#supplementary-material

Module 9: Substance-Related and Addictive Disorders

Case studies: substance-abuse disorders, learning objectives.

• Identify substance abuse disorders in case studies

Case Study: Benny

The following story comes from Benny, a 28-year-old living in the Metro Detroit area, USA. Read through the interview as he recounts his experiences dealing with addiction and recovery.

Q : How long have you been in recovery?

Benny : I have been in recovery for nine years. My sobriety date is April 21, 2010.

Q: What can you tell us about the last months/years of your drinking before you gave up?

Benny : To sum it up, it was a living hell. Every day I would wake up and promise myself I would not drink that day and by the evening I was intoxicated once again. I was a hardcore drug user and excessively taking ADHD medication such as Adderall, Vyvance, and Ritalin. I would abuse pills throughout the day and take sedatives at night, whether it was alcohol or a benzodiazepine. During the last month of my drinking, I was detached from reality, friends, and family, but also myself. I was isolated in my dark, cold, dorm room and suffered from extreme paranoia for weeks. I gave up going to school and the only person I was in contact with was my drug dealer.

Q : What was the final straw that led you to get sober?

Benny : I had been to drug rehab before and always relapsed afterwards. There were many situations that I can consider the final straw that led me to sobriety. However, the most notable was on an overcast, chilly October day. I was on an Adderall bender. I didn’t rest or sleep for five days. One morning I took a handful of Adderall in an effort to take the pain of addiction away. I knew it wouldn’t, but I was seeking any sort of relief. The damage this dosage caused to my brain led to a drug-induced psychosis. I was having small hallucinations here and there from the chemicals and a lack of sleep, but this time was different. I was in my own reality and my heart was racing. I had an awful reaction. The hallucinations got so real and my heart rate was beyond thumping. That day I ended up in the psych ward with very little recollection of how I ended up there. I had never been so afraid in my life. I could have died and that was enough for me to want to change.

Q : How was it for you in the early days? What was most difficult?

Benny : I had a different experience than most do in early sobriety. I was stuck in a drug-induced psychosis for the first four months of sobriety. My life was consumed by Alcoholics Anonymous meetings every day and sometimes two a day. I found guidance, friendship, and strength through these meetings. To say early sobriety was fun and easy would be a lie. However, I did learn it was possible to live a life without the use of drugs and alcohol. I also learned how to have fun once again. The most difficult part about early sobriety was dealing with my emotions. Since I started using drugs and alcohol that is what I used to deal with my emotions. If I was happy I used, if I was sad I used, if I was anxious I used, and if I couldn’t handle a situation I used. Now that the drinking and drugs were out of my life, I had to find new ways to cope with my emotions. It was also very hard leaving my old friends in the past.

Q : What reaction did you get from family and friends when you started getting sober?

Benny : My family and close friends were very supportive of me while getting sober. Everyone close to me knew I had a problem and were more than grateful when I started recovery. At first they were very skeptical because of my history of relapsing after treatment. But once they realized I was serious this time around, I received nothing but loving support from everyone close to me. My mother was especially helpful as she stopped enabling my behavior and sought help through Alcoholics Anonymous. I have amazing relationships with everyone close to me in my life today.

Q : Have you ever experienced a relapse?

Benny : I experienced many relapses before actually surrendering. I was constantly in trouble as a teenager and tried quitting many times on my own. This always resulted in me going back to the drugs or alcohol. My first experience with trying to become sober, I was 15 years old. I failed and did not get sober until I was 19. Each time I relapsed my addiction got worse and worse. Each time I gave away my sobriety, the alcohol refunded my misery.

Q : How long did it take for things to start to calm down for you emotionally and physically?

Benny : Getting over the physical pain was less of a challenge. It only lasted a few weeks. The emotional pain took a long time to heal from. It wasn’t until at least six months into my sobriety that my emotions calmed down. I was so used to being numb all the time that when I was confronted by my emotions, I often freaked out and didn’t know how to handle it. However, after working through the 12 steps of AA, I quickly learned how to deal with my emotions without the aid of drugs or alcohol.

Q : How hard was it getting used to socializing sober?

Benny : It was very hard in the beginning. I had very low self-esteem and had an extremely hard time looking anyone in the eyes. But after practice, building up my self-esteem and going to AA meetings, I quickly learned how to socialize. I have always been a social person, so after building some confidence I had no issue at all. I went back to school right after I left drug rehab and got a degree in communications. Upon taking many communication classes, I became very comfortable socializing in any situation.

Q : Was there anything surprising that you learned about yourself when you stopped drinking?

Benny : There are surprises all the time. At first it was simple things, such as the ability to make people smile. Simple gifts in life such as cracking a joke to make someone laugh when they are having a bad day. I was surprised at the fact that people actually liked me when I wasn’t intoxicated. I used to think people only liked being around me because I was the life of the party or someone they could go to and score drugs from. But after gaining experience in sobriety, I learned that people actually enjoyed my company and I wasn’t the “prick” I thought I was. The most surprising thing I learned about myself is that I can do anything as long as I am sober and I have sufficient reason to do it.

Q : How did your life change?

Benny : I could write a book to fully answer this question. My life is 100 times different than it was nine years ago. I went from being a lonely drug addict with virtually no goals, no aspirations, no friends, and no family to a productive member of society. When I was using drugs, I honestly didn’t think I would make it past the age of 21. Now, I am 28, working a dream job sharing my experience to inspire others, and constantly growing. Nine years ago I was a hopeless, miserable human being. Now, I consider myself an inspiration to others who are struggling with addiction.

Q : What are the main benefits that emerged for you from getting sober?

Benny : There are so many benefits of being sober. The most important one is the fact that no matter what happens, I am experiencing everything with a clear mind. I live every day to the fullest and understand that every day I am sober is a miracle. The benefits of sobriety are endless. People respect me today and can count on me today. I grew up in sobriety and learned a level of maturity that I would have never experienced while using. I don’t have to rely on anyone or anything to make me happy. One of the greatest benefits from sobriety is that I no longer live in fear.

Case Study: Lorrie

Figure 1. Lorrie.

Lorrie Wiley grew up in a neighborhood on the west side of Baltimore, surrounded by family and friends struggling with drug issues. She started using marijuana and “popping pills” at the age of 13, and within the following decade, someone introduced her to cocaine and heroin. She lived with family and occasional boyfriends, and as she puts it, “I had no real home or belongings of my own.”

Before the age of 30, she was trying to survive as a heroin addict. She roamed from job to job, using whatever money she made to buy drugs. She occasionally tried support groups, but they did not work for her. By the time she was in her mid-forties, she was severely depressed and felt trapped and hopeless. “I was really tired.” About that time, she fell in love with a man who also struggled with drugs.

They both knew they needed help, but weren’t sure what to do. Her boyfriend was a military veteran so he courageously sought help with the VA. It was a stroke of luck that then connected Lorrie to friends who showed her an ad in the city paper, highlighting a research study at the National Institute of Drug Abuse (NIDA), part of the National Institutes of Health (NIH.) Lorrie made the call, visited the treatment intake center adjacent to the Johns Hopkins Bayview Medical Center, and qualified for the study.

“On the first day, they gave me some medication. I went home and did what addicts do—I tried to find a bag of heroin. I took it, but felt no effect.” The medication had stopped her from feeling it. “I thought—well that was a waste of money.” Lorrie says she has never taken another drug since. Drug treatment, of course is not quite that simple, but for Lorrie, the medication helped her resist drugs during a nine-month treatment cycle that included weekly counseling as well as small cash incentives for clean urine samples.

To help with heroin cravings, every day Lorrie was given the medication buprenorphine in addition to a new drug. The experimental part of the study was to test if a medication called clonidine, sometimes prescribed to help withdrawal symptoms, would also help prevent stress-induced relapse. Half of the patients received daily buprenorphine plus daily clonidine, and half received daily buprenorphine plus a daily placebo. To this day, Lorrie does not know which one she received, but she is deeply grateful that her involvement in the study worked for her.

The study results? Clonidine worked as the NIDA investigators had hoped.

“Before I was clean, I was so uncertain of myself and I was always depressed about things. Now I am confident in life, I speak my opinion, and I am productive. I cry tears of joy, not tears of sadness,” she says. Lorrie is now eight years drug free. And her boyfriend? His treatment at the VA was also effective, and they are now married. “I now feel joy at little things, like spending time with my husband or my niece, or I look around and see that I have my own apartment, my own car, even my own pots and pans. Sounds silly, but I never thought that would be possible. I feel so happy and so blessed, thanks to the wonderful research team at NIDA.”

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• Benny Story. Provided by : Living Sober. Located at : https://livingsober.org.nz/sober-story-benny/ . License : CC BY: Attribution
• One patientu2019s story: NIDA clinical trials bring a new life to a woman struggling with opioid addiction. Provided by : NIH. Located at : https://www.drugabuse.gov/drug-topics/treatment/one-patients-story-nida-clinical-trials-bring-new-life-to-woman-struggling-opioid-addiction . License : Public Domain: No Known Copyright

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Norén, N., & Sigurd Pilesjö, M. (2016). Supporting a child with multiple disabilities to participate in social interaction: The case of asking a question. Clinical Linguistics and Phonetics, 30(10), 790–811. https://doi.org/10.1080/02699206.2016.1213883   This study examined the multiparty interaction in which a speech language therapist supported a 10-year-old girl with multiple disabilities (i.e., cerebral palsy, moderate … Read more

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• Published: 29 May 2024

Network analysis of comorbid aggressive behavior and testosterone among bipolar disorder patients: a cross-sectional study

• Hong Cai   ORCID: orcid.org/0000-0002-7915-1092 2 ,
• Tian Han 1 ,
• Yi-Fan Wang 1 ,
• Juan Li 1 ,
• Xiao-meng Xie   ORCID: orcid.org/0000-0001-6759-9685 1 &
• Xiao Ji   ORCID: orcid.org/0009-0006-9248-0719 1  

Translational Psychiatry volume  14 , Article number:  224 ( 2024 ) Cite this article

Metrics details

• Bipolar disorder
• Prognostic markers

Testosterone has complex effects on psychological traits and behavior; it is associated with social dominance and competition and is a potential human sex pheromone. This study aimed to investigate the associations between testosterone levels, aggressive behavior, and manic symptoms using a network analysis among bipolar disorder (BD) patients in psychiatric emergency departments (PED). Data from January 2021 and March 2022 BD patients in PED were analyzed. Manic symptoms were assessed using the Young Mania Rating Scale (YMRS). Aggression was assessed with subscale of the PANSS scale (PANSS-AG). The undirected network structures of testosterone levels, aggressive behavior, and manic symptoms were estimated, and centrality and bridge centrality indices were examined. Network stability was examined using the case-dropping procedure. The Network Comparison Test (NCT) was conducted to evaluate whether network characteristics differed by gender. We recruited a total of 898 BD patients, with the mean YMRS score as 13.30 ± 9.58. The prevalence of level II aggression was 35.6% (95%CI = 32.5%–38.7%), level III aggression was 29.5% (95%CI = 26.3%–32.6%), and level VI aggression was 7.0% (95%CI = 5.4%–8.8%). The male participants had a mean testosterone level of 391.71 (Standard Deviation (SD):223.39) compared to 36.90 (SD:30.50) for female participants in the whole sample. Through network analysis, “Increased motor activity-energy” emerged as the central symptom, with the highest centrality expected influence, followed by “Emotional Instability” and “Disruptive/aggression behavior”. Notably, “Emotional Instability” appeared to be the bridge symptom linking manic symptoms to aggressive behavior. Within the flow network model, “Speech rate and amount” exhibited the strongest positive correlation with testosterone levels, followed closely by “Disruptive/aggression behavior”. The constructed network model demonstrated robust stability, with gender showing no significant impact on the structure. In this study, “Increased motor activity-energy” stood out as the most influential symptom, and “Speech rate and amount” acted as the main bridge symptom linking testosterone levels, aggressive behavior, and manic symptoms. Targeting the central and bridge symptoms may improve the outcomes of aggression interventions implemented among BD patients in psychiatric emergency care.

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Introduction.

Bipolar disorder (BD) is a potentially lifelong condition characterized by extreme changes in mood with high incidences of hyperactivity, irritability, grandiosity, poor judgment, and other symptoms, all of which are highly likely to lead to aggressive behavior [ 1 ]. Impulsive aggression is common amongst BD patients. Notably, aggressive behavior in BD patients show a direct prognostic value, which links to suicidal behaviors, more frequent hospitalizations, higher severity of mania symptoms, mixed symptoms, and comorbid borderline personality disorder [ 2 ]. A characteristic of BD emerges as hindrance towards an individual’s ability to perceive risk and protect themselves, which make them vulnerable to physical assault [ 3 ]. Given the risk of hurting others and self-harm, patients with BD have profound effects on society and family numbers.

The etiology of BD is unknown; however, factors such as genetics, biological traits, and environment have been proposed for consideration in the pathogenesis of BD [ 4 ]. For patients with BD who are experiencing disease episode, emergency departments or psychiatric emergency department (PED) are often their preferred choice for medical treatment. The highest prevalence of aggressive behavior occur in acute care settings (12.5–61.8%) [ 5 , 6 ]. Psychiatric emergency department is suitable place to study the relationship for testosterone levels, aggressive behavior, and manic symptoms among patients with BD.

Several lines of evidence indicates that testosterone may be involved in the pathophysiology of aggressive behavior [ 7 , 8 ]. Testosterone, an androgenic steroid hormone that is regulated by the hypothalamus-pituitary-gonadal (HPG) axis, has traditionally been associated with the manifestation of aggression, partly due to its close relationship with dominance behavior and competitive tendencies [ 9 ]. A study reported that administering exogenous testosterone can rapidly increase aggressive behavior in adult males [ 10 ]. Testosterone maintains have a complex relationship with BD; it can impact emotions, with elevated levels of testosterone associated with increasing incidences of depressive and hypomania symptoms [ 11 ]. Some gender differences have been observed with respect to the clinical course in patients with BD [ 12 ]. This evidence suggests a relationship between testosterone levels and aggressive behavior need to be discuss.

Hence, we need to establish a interaction assessment model, which is helpful for understanding the pathogenesis of aggressive behavior in patients with BD. Clinicians could then establish suitable biomarkers for the purposes of screening, risk appraisal, and subsequent therapeutic interventions [ 13 ]. In recent years, network analysis has experienced an expanding application in the field of psychology and psychiatry [ 14 ]. Network analysis is an innovative and analytical method that elucidates a biological system by anticipating the inter-relationships among multiple syndromes [ 15 ]. To further probe the inter-relationship between testosterone and aggressive behavior in BD patients, we incorporated network analysis into this investigation and identify symptoms as robust central symptoms, bridge symptoms and short paths between testosterone and aggrresive behavior within such populations in psychiatric emergency care. We hypothesize that high levels of testosterone may represent a key link point in neurobiological activity, which might contribute to aggression by exacerbating emotional instability.

Patients and study sites

A cross-sectional survey was conducted between January 2021 and March 2022 in Beijing Anding Hospital’s psychiatric emergency department, which is the only 24-h psychiatric hospital emergency service in the Beijing municipality and neighboring provinces. During the study, all patients who had received psychiatric emergency service were recruited consecutively for the survey. Eligible participants had to meet the following criteria: (1) receiving emergency maintenance treatment for a major psychiatric disorder; (2) provided written informed consent; (3) clinical diagnosis of a manic episode (F30–F39 in the ICD-10) (i.e., the Young Mania Rating Scale (YMRS) total score of ≥20 (Ouyang et al. [ 41 ]). Ethical approval was obtained from the Ethics Committee of Beijing Anding Hospital.

The basic socio-demographic and clinical data (e.g., age, onset age, gender, education level, marital status, employment status, illness duration, family history of psychiatric disorders) were collected using a form designed for this study through a review of medical records and confirmation from a clinical interview.

Blood collection and assays of testosterone

The routine blood collections were performed for clinical evaluations during psychiatric emergency visits. Serum samples were collected from all patients between 7:30 AM and 8:30 AM. Controlling for age and gender, the levels of 8 (7.30–8.30) AM serum were assayed for Testosterone (μg/dl) using chemiluminescence. The laboratory personnel were blind to all clinical information. Samples and data were processed following standard operating procedures with the appropriate approval of the Ethics and Scientific Committee of Capital Medical University, and all subjects provided written informed consent.

Measurement

In this study, aggressive behavior was assessed through interviews conducted by a trained attending psychiatrist within 12 h after admission. The aggressiveness of the subjects was graded using the standardized scale delineated by the local health authority and extensively employed in Chinese clinical practice. The severity of aggression is assessed in three domains: verbal aggression, aggression towards property, and physical aggression towards individuals. Verbal aggression, in this context, pertains to yelling or screaming, exhibiting hostile or offensive gestures, or uttering profanities. The standardized scale determines the intensity of each possible form of aggression on a scale of I to VI, with a level above II considered as aggression. We also used the aggression subscale of the PANSS scale (PANSS-AG), which includes supplementary components for the risk aggression profile (such as anger, difficulty in delaying gratification, and emotional instability) [ 16 ]. The PANSS had been validated in the Chinese population and demonstrates satisfactory psychometric properties (Cronbach’s alpha = 0.84) [ 17 ].

The Youth Mania Rating Scale (YMRS) [ 18 ] is an 11-item clinical rating scale used to assess the severity of manic symptoms. Seven of the eleven individual YMRS items were scored on a 0–4 scale: appearance, insight, language-thought disorder, increased motor activity-energy, elevated mood, sleep, and sexual interest, while the remaining four items were scored on a 0–8 scale: disruptive/aggressive behavior, content of morbid thinking, irritability, and speech–rate and amount. The YMRS total score, with a range of 0–60, is a summation of each of the eleven individual scores, with higher total scores signifying a more severe manifestation of mania.

Statistical analyses

Data were analyzed with the IBM Statistical Package for Social Science (SPSS) software version 24.0 and R software version 4.2.3. Normality of the data was assessed using the Kolmogorov–Smirnov test. Using the R software [ 19 ], a network model of aggression severity and testosterone level was built. To examine the edges of the network, we computed the polychoric correlations between all items and estimated the Graphical Gaussian Model (GGM) using the graphic least absolute shrinkage and selection operator (LASSO), and the Extended Bayesian Information Criterion (EBIC) using the R package graph [ 20 ].

The importance of each node in the network was examined by estimating centrality indices of the network structure with the R package “graph” [ 21 ]. Specifically, the centrality index of expected influence (EI) was computed for each node in the network (i.e., the sum of the weights of the connections, in absolute value), because EI is the most stable and interpretable centrality index [ 20 ]. The thickness of the edge represents the strength of the association. Additionally, previous studies [ 22 ] on comorbid psychiatric syndromes found that “Testosterone” was commonly reported to link different symptom communities as a key node. Therefore, the node-specific predictive betweenness of “Testosterone” (i.e., how often a node lies on the pathways between two other nodes, always with the “Testosterone” node as either of them across 1000 nonparametric bootstrap iterations) was estimated [ 23 ]. To identify particular symptoms that were directly associated with “Testosterone”, the “flow” function in the R package ‘qgraph’ was used [ 21 ].

Following previous studies [ 24 , 25 ], the differences in network characteristics between male and female participants were compared using the R “NetworkComparisonTest” package (Version 2.2.1) [ 26 ] with 1000 permutations. The difference in network structure (e.g., distributions of edge weights), global strength (e.g., total absolute connectivity among the symptoms), and each specific edge between subsamples (i.e., females vs. males) were also examined.

A total of 915 patients were invited to participate in this study; 898 patients met the study criteria and were included in analyses, in which the response rate was 98.1%, the rest of them were not included in the analysis due to incomplete information. The prevalence of level II aggression was 35.6% (95%CI = 32.5%–38.7%), level III aggression was 29.5% (95%CI = 26.3%–32.6%), and level VI was 7.0% (95%CI = 5.4%–8.8%). The male participants had a mean testosterone level of 391.71 ± 223.39 ng/dl (reference range 260–1590 ng/dl for ♂) compared to 36.90 ± 30.50 ng/dl for female participants (reference range 15–80 ng/dl for ♀). The demographic and clinical characteristics of the study population are summarized in Table 1 .

Network structure

Figure 1 illustrates the network structure representing the comorbid severity of aggression, manic symptoms, and testosterone levels in participants diagnosed with BD. The network model reveals that the strongest positive association among manic symptoms is between YMRS1 (“Elevated mood”) and YMRS2 (“Increased motor activity-energy”), followed by YMRS7 (“Language-thought disorder”) and YMRS8 (“Content of morbid thinking”), as well as YMRS5 (“Irritability”) and YMRS9 (“Disruptive/aggression behavior”).

AS aggression severity, FE facial expression, SI anger, S2D delyed graftification, S3E Emotional instability, T testosterone, YMRS1 high mood, YMRS2 increased behavioral activity, YMRS3 sexual interest, YMRS4 sleep, YMRS5 ittitability, YMRS6 language speed and quantity, YMRS7 language thinking disturbed, YMRS8 patients thinking, YMRS9 attack and sabotage, YMRS10 appearance, YMRS11 self-control.

Regarding EI centrality, the node YMRS2 (“Increased motor activity-energy”) exhibits the highest value, followed by S3E (“Emotional instability”) and YMRS9 (“Disruptive/aggression behavior”) within the network (Fig. 1 ). In terms of bridge EI, S3E (“Emotional instability”) emerges as the most critical bridge symptom connecting aggression and manic symptoms, succeeded by YMRS9 (“Disruptive/aggression behavior”) and S2D (“Delaying gratification”) (Fig. 1 ). Furthermore, the flow network model demonstrates that YMRS6 (“Speech–rate and amount”) exhibits the strongest positive correlation with testosterone, followed by YMRS1 (“Elevated mood”) (Fig. 2 ). In addition, we found that YMRS6 (“Speech–rate and amount”) has the strongest positive association with testosterone in the flow network model, followed by the YMRS1 (“Elevated mood”) (Fig. 2 ).

Flow network of Testosterone.

Regarding network stability, the EI centrality demonstrates an exceptional level of stability (i.e., CS-coefficient = 0.75 (95% CI: 0.675-1)), indicating that the network structure would not change significantly even if 75% of the sample was removed (Fig. 3 ). The bootstrap difference test revealed that most comparisons between edge weights were statistically significant.

The stability of centrality and bridge centrality indices using case-dropping bootstrap.

Node-specific predictive betweenness measure

Researchers have found that “Testosterone” plays an important role in aggressive behavior in previous studies [ 22 ]. Figure 4 shows the node-specific predictive betweenness values for each node in the network. The white dots represent the node-specific predictive betweenness in the study sample, while the black lines represent the variability of the measure across 1000 nonparametric bootstrap iterations. YMRS6 (“Speech–rate and amount”) has the highest node-specific predictive betweenness score, followed by YMRS5 (“Irritability”). This finding suggests that “Speech–rate and amount” and “Irritability” may be the main bridge symptoms between testosterone levels, manic symptoms, and aggression (Fig. 4 ).

Node-specific predictive betweenness.

Network comparison tests by gender

The comparison of the network model by gender did not reveal significant differences in network global strength (network strength: 11.37 in female participants; 11.40 male participants; M = 0.214, P = 0.571) and edge weights (S = 0.026, P = 0.969, Supplementary Figs. S1 – S4 ).

The study is the first network analysis of the association between testosterone levels and aggressive behavior among patients with BD in China PED. Within the assessed network model, “Increased motor activity-energy”, “Emotional instability” and “Disruptive/aggressive behavior” stood out as the most influential symptoms. Notably, “Speech rate and amount” acted as the main bridge symptom linking testosterone levels, manic symptoms, and aggression, followed by “Elevated Mood” and “Difficulty in delaying gratification”.

Our network analysis highlighted “Increased motor activity-energy” and “Emotional instability” as central symptoms in patients arriving at the emergency room due to aggressive tendencies. Patients with BD often displays alcohol or substance abuse, which can increase behavioral activity, leadings to an increased prevalence of aggressive behavior possibly up to 12% [ 27 ]. Consistent with previous findings, aggression was associated with more severe manic symptoms, as measured by the YMRS in acute manic episodes [ 28 ]. People in the manic phase are often highly motivated to engage in goal-oriented activities. However, due to lack of insight, patients may not realize their behavior is abnormal and prone to harmful consequences. Patients become extremely aggressive and irritable, and are more likely to harm themselves or others and destroy property through verbal or physical aggression [ 29 ]. This observation also shed light on the identification of “Difficulty in delayed gratification” as another bridge symptom. Previous functional magnetic resonance imaging (fMRI) studies have observed responses in the amygdala, periaqueductal gray matter, and the prefrontal lobe when BD patients were frustrated by the denial of a reward. This neural response can potentially stimulate aggressive impulses, transforming unfulfilled desires into the urge to attack [ 30 ].

“Speech–rate and amount” acted as the main bridge symptoms linking testosterone levels, manic symptoms, and aggression, succeeded by “Elevated Mood”. “Speech–rate and amount” and “Elevated mood” are typical symptoms of manic episodes, and previous imaging studies have shown abnormalities in neuronal coupling in the sensory-motor subcortical-cortical circuit in patients with highly excited brains, compared to healthy controls [ 31 ]. Testosterone may act through receptors located in key regulatory regions to increase the connectivity between subcortical regions of the brain while weakening connections between the cortex and subcortical regions [ 32 ], causing the patient in highly excited state. Abnormal regulation of the HPG axis is critical for homeostatic regulation of synthesis and secretion of testosterone and the most potent androgen dihydrotestosterone (DHT) by the testis [ 33 ]. Dysregulation of the HPG axis may cause depressive symptoms, which are associated with high cortisol inhibition [ 34 ]. Moreover, compared to bodybuilders who did not take exogenous testosterone, there was a higher rate of hypomanic episodes among those who did [ 35 ]. The release of testosterone will increase the motivation of BD patients to seek dominance and take impulsive risks, which are often poorly thought-out and prone to adverse consequences [ 36 ]. High levels of testosterone have been found to reduce activity and functional connectivity in the prefrontal cortex, altering the function of prefrontal-mediated emotion regulation, thereby impairing the ability to control aggressive impulses [ 37 ].

Regarding the gender for the network model of comorbid aggression severity, manic symptoms, and testosterone levels among patients with BD, there were none significant differences shown in this study. The existing evidence suggests that testosterone concentrations in early life influence the development of some human behaviors, with certain gender differences [ 38 ]. One study from community recruiters suggested that adolescent males with higher plasma testosterone levels were more irritable and likely to overreact to provocation and threats [ 39 ]. Previous studies on depressive episode status in patients with BD have found that male patients have significantly lower testosterone levels, while female patients have significantly higher levels [ 40 ].

The strengths of this study include a substantial sample size, the utilization of standardized assessment instruments, and the employment of network analysis techniques. These techniques were tailored to investigate the structure of the model assessing testosterone levels and aggressive behavior in patients with BD. Such insights may pinpoint potential targets for treatment and prevention measures, particularly for patients with BD in psychiatric emergencies exhibiting these problems. Nonetheless, several methodological limitations in our study warrant attention. First, the cross-sectional design precludes establishing causal relationships between variables, and there was an absence of a control/naive group. Future longitudinal research is essential to elucidate the time-bound causal links between testosterone levels and aggressive behavior in patients with BD. Secondly, though routine blood collections were performed for clinical evaluations during psychiatric emergency visits, additional measurements, such as thyroxine, should be added to the study analysis. Subsequently, we hope to carry out relevant radiological research to further explore the specific relationship between testosterone levels and aggressive behavior in BD patients. Lastly, our sample was consecutively drawn from one major psychiatric emergency department (PED) in China, which may limit the generalizability of our findings in other psychiatric contexts.

To summarize, within the aggression-bipolar disorders network model, as well as the association with testosterone levels, “Increased motor activity-energy,” “Emotional instability,” and “Disruptive/aggressive behavior” were the most pivotal symptoms among BD patients in PED. Our study showed no significant gender differences in testosterone levels observed in BD patients during the manic episode phase. These specific symptoms, which are potential intervention targets, should be at the forefront of physicians’ evaluation protocols.

Data availability

The data of the investigation will be made publicly available if necessary.

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The study was supported by the National Clinical Key Specialty Construction Project Fund (3-2-2021-PT40).

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Yi Liu, Tian Han, Yi-Fan Wang, Juan Li, Xiao-meng Xie & Xiao Ji

Unit of Psychology Medicine and Behavior Medical, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China

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(I) Conception and design: Xiao Ji, Xiao-meng Xie. (II) Administrative support: Xiao Ji, Yi Liu, Yi-Fan Wang. (III) Provision of study materials or patients: Cai Hong, Yi Liu, Tian Han, Juan Li. (IV) Collection and assembly of data: Yi-Fan Wang, Yi Liu, Tian Han, Juan Li. (V) Data analysis and interpretation: Yi-Fan Wang, Xiao-meng Xie, Cai Hong. (VI) Manuscript writing: All authors. (VII) Final approval of manuscript: All authors.

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This study involving human participants was reviewed and approved by the Human Research and Ethics Committee of Beijing Anding Hospital, Capital Medical University. All the study procedures were carried out in accordance with relevant guidelines. The approval number is 2022(163)-202314FS-2.

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Liu, Y., Cai, H., Han, T. et al. Network analysis of comorbid aggressive behavior and testosterone among bipolar disorder patients: a cross-sectional study. Transl Psychiatry 14 , 224 (2024). https://doi.org/10.1038/s41398-024-02957-1

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Published : 29 May 2024

DOI : https://doi.org/10.1038/s41398-024-02957-1

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Study considers human medicine for answers on common canine immune disease

• Sarah Boudreau

29 May 2024

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Like many other 3-year-old dogs, Oakley is full of energy. After coming back to her home in Beckley, West Virginia, after a run one day, everything seemed normal — but suddenly, Oakley’s nose started dripping blood. 

Oakley is a rambunctious, “accident-prone” Doberman pinscher pup who gets knicks and scratches all the time and has never had a problem before, so the sudden, unstoppable bleeding terrified her owners, MacKenzie Milam and her mother Jennifer Milam. 

After driving to multiple clinics, Oakley and her owners landed at the Virginia-Maryland College of Veterinary Medicine ’s Veterinary Teaching Hospital (VTH) in the early hours of the morning.

Oakley didn’t lose any of her pep and playfulness, but she kept bleeding. At the VTH, the internal medicine team determined that Oakley had a disorder called immune-mediated thrombocytopenia (ITP). With medication, Oakley’s bleeding subsided.

When MacKenzie and Jennifer learned that assistant professor of small animal internal medicine Ashley Wilkinson is conducting a study on ITP, they jumped at the chance to enroll her. 

"If you can help someone, or another animal, by all means,” Jennifer Milam said. 

Research into ITP has the potential to help many dogs, as canine ITP is a common disorder, and it’s one of the top causes of a low platelet count in dogs. 

"We see ITP very frequently in the hospital — there are many happy cases, but there are unfortunately also sad ones, so there's a lot of work to be done there," said Wilkinson.

ITP is an autoimmune disorder where the immune system destroys platelets, blood cells that bind together to stop bleeding. Most dogs are diagnosed with ITP after a scary, unstoppable bleeding incident like in Oakley's case, but some dogs are diagnosed after routine bloodwork finds an unexplainably low platelet count.

This discrepancy piqued Wilkinson's interest. 

"With ITP in dogs, there's a huge spectrum in terms of presentation — some will be very stable and won't even have bleeding tendencies, and some will be very critical in the ICU with multiple blood transfusions, and some won't make it. It seems that the platelet count doesn't dictate what they look like clinically — it seems that there's something we're missing that affects their clinical picture," said Wilkinson.

The answer may lie in human medicine. In humans, it's difficult to differentiate between ITP and immune thrombotic thrombocytopenic purpura (iTTP), a diagnosis that does not exist in dogs. 

Humans with iTTP have a deficiency of an enzyme called ADAMTS13 that's responsible for breaking down proteins that help with blood clotting called von Willebrand factor. With von Willebrand factor unchecked, blood clots excessively, resulting in a low platelet count due to the platelets being used excessively in the blood clots. Paradoxically, people with iTTP experience problems with both blood clots and excessive bleeding. 

Wilkinson's study looks at the levels of ADAMTS13 in dogs with ITP, exploring the possibility that some dogs diagnosed with ITP may in fact have a different disorder similar to iTTP in humans.

"We typically use animal models to help us understand human disease, but in this case, humans are helping us consider this as a disease in animals," explained Sierrah Travis , a small animal internal medicine resident who also works on the study.

If they find that some dogs with ITP have low ADAMST13, it could kick off more research that could yield new, more effective treatments for those dogs who struggle with low platelets and bleeding problems. 

That means more happy endings like Oakley’s.

Thanks to treatment and routine blood tests to monitor her ITP, Oakley has bounced back. Her owners report that she's had incidents where she's had nicks and scratches, and her blood has clotted like normal. 

"We’re so happy she’s doing well — these success stories really warm our hearts,” said Travis.

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Candidate Genes from an FDA-Approved Algorithm Fail to Predict Opioid Use Disorder Risk in Over 450,000 Veterans

• PMID: 38798430
• PMCID: PMC11118646
• DOI: 10.1101/2024.05.16.24307486

Importance: Recently, the Food and Drug Administration gave pre-marketing approval to algorithm based on its purported ability to identify genetic risk for opioid use disorder. However, the clinical utility of the candidate genes comprising the algorithm has not been independently demonstrated.

Objective: To assess the utility of 15 variants in candidate genes from an algorithm intended to predict opioid use disorder risk.

Design: This case-control study examined the association of 15 candidate genetic variants with risk of opioid use disorder using available electronic health record data from December 20, 1992 to September 30, 2022.

Setting: Electronic health record data, including pharmacy records, from Million Veteran Program participants across the United States.

Participants: Participants were opioid-exposed individuals enrolled in the Million Veteran Program (n = 452,664). Opioid use disorder cases were identified using International Classification of Disease diagnostic codes, and controls were individuals with no opioid use disorder diagnosis.

Exposures: Number of risk alleles present across 15 candidate genetic variants.

Main outcome and measures: Predictive performance of 15 genetic variants for opioid use disorder risk assessed via logistic regression and machine learning models.

Results: Opioid exposed individuals (n=33,669 cases) were on average 61.15 (SD = 13.37) years old, 90.46% male, and had varied genetic similarity to global reference panels. Collectively, the 15 candidate genetic variants accounted for 0.4% of variation in opioid use disorder risk. The accuracy of the ensemble machine learning model using the 15 genes as predictors was 52.8% (95% CI = 52.1 - 53.6%) in an independent testing sample.

Conclusions and relevance: Candidate genes that comprise the approved algorithm do not meet reasonable standards of efficacy in predicting opioid use disorder risk. Given the algorithm's limited predictive accuracy, its use in clinical care would lead to high rates of false positive and negative findings. More clinically useful models are needed to identify individuals at risk of developing opioid use disorder.

Key points: Question: How well do candidate genes from an algorithm designed to predict risk of opioid use disorder, which recently received pre-marketing approval by the Food and Drug Administration, perform in a large, independent sample? Findings: In a case-control study of over 450,000 individuals, the 15 genetic variants from candidate genes collectively accounted for 0.4% of the variation in opioid use disorder risk. In this independent sample, the SNPs predicted risk at a level of accuracy near random chance (52.8%). Meaning: Candidate genes from the approved genetic risk algorithm do not meet standards of reasonable clinical efficacy in assessing risk of opioid use disorder.

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