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 Tales From the Clinic: The Art of Psychiatry, 

we discuss delirium, an underrecognized, underdiagnosed medical condition. Elderly patients, who experience more delirium than their younger counterparts, often receive a misdiagnosis. They may be mistakenly labeled as having a mental illness and given psychotropic medications that have an elevated adverse effect burden.

“Mr Morris,” aged 70, had melanoma and, following treatment, is in remission. Mr Morris presents to your outpatient psychiatry clinic for an initial evaluation. He has never had medical issues otherwise and has never been diagnosed with a mental illness until a hospital stay about 6 months ago. His family provided collateral information. They were very concerned because, while he was hospitalized, he was “talking nonsense” and accusing his wife of 50 years of having an extramarital affair. He was also pacing and saying random things about memories which they thought were made up, such as the example above. Inquiring about this in your clinical assessment, the patient says, with some bashfulness, “Well, you know, we met at 15 and a lot of people liked her. I was the lucky one.” But he does not recall anything he said while hospitalized. He was discharged on haloperidol, but the family stopped it after reading about the black box warning for antipsychotics in older adults. A careful history taking is negative for psychotic symptoms including 

, and disorganization, and for negative symptoms of psychosis. Since being home and off medications, he is back to his usual self.

You ask for medical records and find out that the medication was started after an episode during which the psychiatry consult and liaison service consulted for overnight confusion and agitation. Mr Morris had started to pull out his IV lines and catheter, then tried to undress and walk down the hallway, but was falling down, given physical weakness. The medication was not stopped upon symptom resolution and patient discharge.

Mr Morris is diagnosed with delirium. According to the DSM-5, delirium is “a disturbance in attention and awareness” with an additional cognitive disturbance (eg, memory deficit, disorientation, language, visuospatial ability or perception) that develops over “hours to a few days,” “represents a change from baseline,” and “fluctuates in severity during the course of a day.” Furthermore, it is due to 1 or multiple underlying medical etiologies and is not better explained by another psychiatric diagnosis.

: hyperactive, hypoactive, and mixed. In our vignette, the acute agitation and interference with medical treatment quickly brings this patient to staff attention. However, the literature shows that delirium is missed in 57% to 83% of emergency department (ED) assessments, and in admitted patients, more than 90% of cases will be missed if it is not diagnosed in the ED.

 According to a prospective study in The University of Texas MD Anderson Cancer Center Emergency Medicine department, patients with cancer who presented with delirium are more likely to be admitted to the hospital, require an ICU admission, and have worse outcomes.

 In a retrospective chart review of 61 consecutive inpatient 

 consultations in patients with cancer, 16% of the consultations were for delirium, yet delirium was diagnosed by the palliative care team in 56% of the patients.

 In patients with advanced cancer, terminal delirium prevalence rates approach 90% in 

, its treatment (ie, radiation, chemotherapy), and noncancer-related pathology. In delirium, there are unmodifiable factors that predispose a patient to developing the condition and there are precipitating factors that can be clinically addressed. Common predisposing factors that increase the risk of developing delirium include older age, a neurocognitive disorder, visual and hearing impairments, and chronic organ dysfunction. Precipitating factors to consider include psychoactive medications (including opioids and corticosteroids), infections, hypoxia, withdrawal, metabolic derangement, dehydration, and acute infections, especially 

, the precipitating cause or causes should be treated. Lawlor studied delirium in patients with advanced cancer and determined that reversibility was most common when addressing the precipitating factors of psychoactive medications, specifically 

 The pathophysiology of delirium is complex, and there are hypotheses to explain the role of 

, oxidative stress, and neurotransmitters in the condition. Delirium is a state of low acetylcholine and high dopamine, which is important to consider when reviewing if a medication could be contributing to a patient’s delirium.

Psychoactive medications include opioids, 

, antidepressants, antihistamines, and anticholinergics. When delirium develops, it is important to consider these medications as potential precipitating factors. Anticholinergics and antihistamines commonly worsen delirium and should be discontinued. The duration of use and dose of benzodiazepines should be closely examined in 

 because the sudden cessation of a medication on which a patient is dependent could produce a withdrawal delirium; however, ongoing use in a patient without tolerance could result in intoxication.

 are frequently used for cancer-related pain. However, opioid toxicity can occur, especially with rapid dose escalation for pain control. Medication adjustments including opioid rotation are helpful in managing opioid toxicity and managing pain when side effects limit further uptitration.

 Opioid rotation is the practice of transitioning to a different opioid with the goal of optimizing the balance of pain control to side effects. The clinical practice guidelines for the European Society for Medical Oncology recommend opioid rotation, which can allow for dose reduction given opioid equianalgesic dosing.

Corticosteroids are more likely to have psychiatric sequelae at higher doses. Findings from 1 study revealed that the rate of psychiatric reactions is 1.3%, 4.6%, and 18.4% at doses of prednisone less than 40 mg/day, 41 to 80 mg/day, and greater than 80 mg/day, respectively.

, psychosis, and delirium can develop in the acute course of corticosteroid use. Depression, which is part of the differential diagnosis for hypoactive delirium, is more likely to develop with chronic steroid use.

 Although corticosteroids can contribute to delirium, they can also improve cognition by decreasing edema secondary to primary or metastatic brain tumors.

 It is important to consider the timeline of symptom development and treatment when considering the impact of corticosteroids in delirium. Delirium secondary to corticosteroid exposure is likely to occur within 1 to 2 weeks and at a higher incidence for higher doses.

Furthermore, delirium caused by corticosteroids has been associated with delirium-related distress.

 As clinically indicated, minimizing the dose and duration of treatment can improve delirium related to steroid administration.

Delirium is treated by correcting the precipitating factors; however, nonpharmacologic and pharmacologic strategies are used to assist in its management. Nonpharmacologic management includes frequent reorientation, patient access to glasses and hearing aids, familiar surroundings (consistent care team, family present or their pictures available), regulating sleep/wake cycles (lights on and blinds open the during day, but lights off and blinds closed at nighttime), clustering care to daytime hours, minimizing lines including IVs and urinary catheters, and encouraging patient mobilization.

 Regarding pharmacologic management, a 2018 Cochrane review of antipsychotic treatment in non-ICU delirious patients concluded that the current evidence to recommend for or against the use of antipsychotics is of low quality, as 

 had no statistically significant impact on delirium resolution or severity.

 In clinical practice, pharmacologic management with antipsychotics is primarily used to target distressing agitation, hallucinations, and delusions. In refractory agitated delirium, the involvement of palliative care and palliative sedation can also be considered.

During the investigation into the etiology and treatment of delirium in a patient, it is important to consider the goals of care. When goals of care are addressed early, a patient’s wishes are known to the team and the substitute decision maker if a patient’s mentation becomes altered. Established goals of care at the end of life allow palliation while limiting more aggressive interventions if it is the patient’s desire. Aggressive interventions at end of life have been associated with worse patient quality of life and worse 

It is always important to remember to consider the system you are treating, which is more than the patient. Breitbart et al showed that 53.5% of delirious patients recalled their delirium. Predictors of patients not recalling their delirium are greater “short-term memory impairment during the 

, the severity of the delirium episode itself, and the presence of perceptual disturbances.” However, more severe hallucinations and delusions, corticosteroid-induced delirium, and poorer Karnofsky Performance Status (KPS) Scale scores were correlated with more delirium-related distress for patients.

 Caregivers are more likely to be distressed when the patient has a hyperactive delirium, brain metastases, and KPS scores below 30, which indicate “severe physical debilitation and near death.” Nursing staff are more likely to be distressed when a delirious patient has more severe delirium and hallucinations.

 While treating the delirium, consider the potential traumatic impact upon the patient, family, and staff, and offer ongoing support.

is a psychiatrist at Baylor College of Medicine in Houston, Texas, and a psychosomatic medicine specialist.

Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition.

2. Han JH, Wilson A, Vasilevskis EE, et al. 

Diagnosing delirium in older emergency department patients: validity and reliability of the delirium triage screen and the brief confusion assessment method.

3. Elsayem AF, Bruera E, Valentine A, et al. 

Advance directives, hospitalization, and survival among advanced cancer patients with delirium presenting to the emergency department: a prospective study.

4. Braiteh F, El Osta B, Palmer JL, et al. 

Characteristics, findings, and outcomes of palliative care inpatient consultations at a comprehensive cancer center.

Delirium in patient with cancer: assessment, impact, mechanisms and management.

6. Lawlor PG, Gagnon B, Mancini IL, et al. 

Occurrence, causes, and outcome of delirium in patients with advanced cancer: a prospective study.

7. ESMO Guidelines Committee. Guidelines. European Society for Medical Oncology. Accessed November 22, 2021. 

8. Kenna HA, Poon AW, de los Angeles CP, Koran LM. 

Psychiatric complications of treatment with corticosteroids: review with case report.

The delirium experience: delirium recall and delirium-related distress in hospitalized patients with cancer, their spouses/caregivers, and their nurses.

10. El Majzoub I, Abunafeesa H, Cheaito R, et al. 

Management of altered mental status and delirium in cancer patients.

11. Burry L, Mehta S, Perreault MM, et al. 

Antipsychotics for treatment of delirium in hospitalized non-ICU patients.

Associations between end-of-life discussions, patient mental health, medical care near death, and caregiver bereavement adjustment. 

Delirium: an underrecognized, underdiagnosed medical condition. 

Delirium: Don’t Miss It

The goal of this activity is to better appreciate the controversies surrounding Lyme disease as well as methods to treat the neuropsychiatric sequela.

• Understand the controversies surrounding Lyme disease diagnosis and treatment, including perspectives of different medical communities and patient communities

• Describe common neuropsychiatric presentations of and treatment options for Lyme disease and of posttreatment Lyme disease (PTLD)

This accredited continuing education (CE) activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals seeking to improve the care of patients with mental health disorders.

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Physicians’ Education Resource®, LLC, designates this enduring material for a maximum of 1.5 

™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

This activity is funded entirely by Physicians’ Education Resource®, LLC. No commercial support was received.

This accredited CE activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this accredited CE activity is for continuing medical education purposes only and is not meant to substitute for the independent clinical judgment of a physician relative to diagnostic or treatment options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual faculty members and do not reflect those of Physicians’ Education Resource®, LLC.

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 and include “Lyme Disease in Psychiatry: Controversies, Chronic Symptoms, and Recent Developments” in the subject line.

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Since its first appearance in a group of children in Old Lyme, Connecticut in the late 1970s, 

 has proliferated throughout the United States and abroad. Only 30,000 to 40,000 cases are reported to the Centers for Disease Control and Prevention (CDC) per year, although recent studies looking at the time period between 2010 and 2018 estimate the actual number to be more than 10 times higher at approximately 476,000.

 Lyme disease is transmitted when an infected tick bites a human and injects the causative bacteria, 

, into the skin. The majority of transmission in the United States occurs in the Northeast, mid-Atlantic, and upper Midwest, as shown in 

 While 70% to 80% of patients develop an erythema migrans rash,

 the majority of these rashes do not have the classic “bull’s-eye” appearance. Other patients may not recall seeing a rash and may have a flu-like illness with such mild symptoms that they do not seek medical attention. Left untreated, Lyme disease can cause wide-ranging effects, including 

, cranial nerve palsy, meningitis, depression, and 

Even after appropriate diagnosis and antibiotic treatment, some patients continue to experience longer-term symptoms, including 

, cognitive problems, or musculoskeletal pain in a condition known as posttreatment Lyme disease syndrome (PTLDS), sometimes also called posttreatment Lyme disease (PTLD). Studies suggest that approximately 10% to 20% of patients who are treated for Lyme disease with the recommended 2- to 4-week course of antibiotics continue to have nonspecific symptoms afterwards.

The Infectious Disease Society of America (IDSA), American Academy of Neurology (AAN), and American College of Rheumatology (ACR) published joint “2020 Guidelines for the Prevention, Diagnosis and Treatment of Lyme Disease”

 that included commentary on the terminology chronic Lyme disease, commonly used in the patient community, expressing concern that it lacks an accepted definition and is applied to a highly heterogeneous population who may have weak clinical or laboratory evidence to confirm prior infection with 

. Although the IDSA had previously developed provisional criteria for the more specific subgroup of PTLD, a term preferred by some researchers as it suggests a well-documented prior diagnosis of Lyme disease, they do not mention this term in their latest guidelines and instead refer to “persistent or recurring nonspecific symptoms such as fatigue, 

, or cognitive impairment following recommended treatment for Lyme disease.”

 There continues to be debate and conflict among patients, providers, and researchers about appropriate terminology for patients with chronic symptoms.

The Scope of the Problem and the “Lyme Wars”

There has been conflict and controversy surrounding Lyme disease since its earliest days. In 1970s Connecticut, mothers of children with unusual arthritis symptoms were angered due to feeling dismissed or ignored by public health officials after little was initially done when they told the officials of this unusual clustering of children with arthritis. In the decades following, intense disagreement continued among professional organizations, community doctors, and patients about what is required for a diagnosis of Lyme disease and what constitutes adequate treatment. The most pressing debates today involve how to treat PTLDS.

The recent joint IDSA/AAN/ACR guidelines recommend against repeat antibiotic treatment for patients with persistent or recurring nonspecific symptoms (eg, fatigue) who do not have objective evidence of reinfection with 

 The guidelines define objective evidence of persistent infection or treatment failure as signs of disease activity such as arthritis, meningitis, or neuropathy.

The International Lyme and Associated Diseases Society (ILADS) guidelines (

) recommend “patients with persistent symptoms and signs of Lyme disease be evaluated for other potential causes before instituting additional antibiotic therapy”; however they advocate for “… antibiotic retreatment when a chronic Lyme infection is judged to be a possible cause of the ongoing manifestations and the patient has an impaired quality of life.”

 Some providers adhere to the more rigid IDSA/AAN/ACR guidelines and others follow the more flexible ILADS guidelines, sometimes leading to heated debate. Such debates have also involved patients and their advocates who can feel dismissed or disbelieved. Amid this charged climate that the media have referred to as the “Lyme wars,” physicians and patients alike can feel frightened, alienated, and overwhelmed.

Given the substantial overlap in symptomatology between Lyme disease and common psychiatric disorders, as well as the psychological effects that can result from a 

, many psychiatrists will see patients with documented or suspected Lyme disease. It is important for psychiatrists to keep Lyme disease on their list of differential diagnoses, to be familiar with diagnostic and treatment strategies, and to understand the challenges patients and providers face due to this complex illness. The following case and text will highlight signs and symptoms to look for, as well as diagnostic strategies and management approaches for such patients.

“Christina,” aged 45 years, is a mother of 2 children who presented reporting several months of low mood, fatigue, subjective memory problems, and headaches. She tearfully explained that she could barely function and reported feeling dismissed by her primary doctor. Christina briefly saw a therapist in college for stress related to a relationship breakup, but she otherwise has had no history of psychiatric treatment. She had a recent unremarkable exam, including vitals and basic blood work, by her primary doctor, who referred her to the psychiatry department for 

Christina was started on sertraline 50 mg with some mild improvement in low mood, but had ongoing fatigue, memory issues, and 

. On further discussion, you learned that 3 months prior, Christina visited family in Massachusetts for the July 4th holiday. She remembered returning from the party with a flu-like illness, but she tested negative for COVID-19 infection and on a Lyme enzyme-linked immunosorbent assay (ELISA) antibody test the following week. She did not recall having any tick bites or rashes. After you discussed the case with Christina’s primary doctor, he ordered a repeat Lyme ELISA antibody test, which yielded positive results. She was then given a confirmatory immunoglobulin (Ig) -G Western blot test, which also yielded positive results.

Christina received treatment with a course of doxycycline and experienced improvement in her fatigue, headaches, and mood. Two months later, she returned with worsening fatigue and headaches. Looking to the IDSA/AAN/ACR guidelines, Christina’s primary doctor recommended against retreatment with 

, as he felt there was no clear evidence of reinfection or persistent infection. Christina sought a second opinion from another community physician, who did additional lab testing—including cerebrospinal fluid (CSF) studies—to evaluate for tick-borne coinfections and autoimmune disease. Workup was unremarkable, but given her severe symptoms, he treated her with courses of doxycycline and amoxicillin, and her fatigue and headaches improved. However, she continued to struggle with low mood, leading to conflict with her family. She ultimately improved with increasing sertraline to 150 mg and a course of individual therapy with several family meetings.

Lyme disease can develop after an infected 

 tick bites human skin. Usually, at least 36 hours, and sometimes up to 72 hours of attachment is required to transmit the infection. Notably, 

 ticks may also transmit other infections, including 

, and others. In 70% to 80% of Lyme cases, an erythema migrans rash will develop at the site of the bite, often within 3 to 32 days.

 The rash typically starts as a red patch, that measures approximately 2 or more inches in diameter. This rash is not painful, but it expands over time and may have satellite rashes. As it grows, the initial patch may develop a central clearing, giving it a classic bullseye appearance (

). Most often, Lyme disease rashes do not have the bull’s-eye appearance and a significant percentage of patients do not recall having a rash at all.

Dissemination of infection beyond the initial localized area can result in a multitude of other symptoms in the following weeks to months. Because the initial immunologic response to Lyme disease involves the release of cytokines, many patients will experience moderate to severe flu-like symptoms during the early disseminated phase of infection (

). A flu-like illness during the summer months in a Lyme disease–endemic area should always raise suspicion for possible 

 infection. Patients may also experience arthralgias and myalgias; these typically affect large joints and often migrate from 1 joint or muscle to another. When acute Lyme infection targets the nervous system, the patient could develop a myriad of conditions (

). Less commonly, Lyme disease can also affect the liver to cause a mild hepatitis, the eyes to cause conjunctivitis, and the heart to cause myocarditis or atrioventricular conduction block.

Months to years later, if Lyme disease goes untreated, patients may experience late disseminated–stage symptoms, many of which can overlap with symptoms of primary psychiatric illness. Such patients may develop neurological problems that include 

, encephalomyelitis, and neuropsychiatric symptoms that are less common in the earlier phases of the disease. Lyme encephalopathy involves cognitive problems, specifically impacting short-term memory, verbal fluency, and processing speed, as well as a subjective feeling of brain fog or feeling mentally slowed down. Rarely, it may involve moderate to severe memory loss and personality changes. Lyme encephalomyelitis may result in confusion, hallucinations, 

, mania, abnormal movements, lack of coordination, or seizures. Less dramatic, but more common, are the neuropsychiatric symptoms, such as depression and anxiety, that occur in 40% of individuals with disseminated Lyme disease either before or after initial antibiotic treatment (

, anger outbursts, and symptoms of obsessive-compulsive disorder are uncommon, although they have been reported. A recent nationwide retrospective cohort study in Denmark by Fallon et al demonstrated that individuals with Lyme borreliosis after a hospital-based diagnosis had increased rates of any mental disorder, of affective disorders, of suicide attempts, and of 

 compared to those without Lyme borreliosis.

Although psychiatric problems can arise during the illness course, it is important to communicate to patients that most psychiatric symptoms in the general population are unrelated to Lyme disease. Treatment of such potentially disabling psychiatric disorders should not be delayed while trying to determine whether or not a patient has Lyme disease. Patients with preexisting anxiety may catastrophize and hyper-focus on information from the media that presents the most frightening consequences of their possible Lyme disease. It may be helpful to explain that whether or not a patient has Lyme disease, treatment of any cooccurring psychiatric disorder, such as major depression or panic disorder, is an essential part of the path to health.

It is also important to note that anchoring to Lyme disease early on, to the exclusion of consideration of other possibilities, can delay diagnosis of other serious medical conditions. The differential diagnosis for neuropsychiatric Lyme disease and PTLDS is wide and includes other tick-borne diseases, psychiatric disorders, autoimmune disease, multiple sclerosis, 

, fibromyalgia, and others. A 2015 case series published in 

 described patients who were misdiagnosed as having persistent symptoms after Lyme disease, but actually had different malignancies, including pituitary adenoma and Hodgkin’s lymphoma.

 Thus, ensuring that patients have had a thorough medical evaluation and follow-up is critical.

The ideal diagnostic test for Lyme disease would clearly indicate the presence of 

 and activity or resolution of infection. Unfortunately, available tests fall short of this ideal, leading to conflict over diagnosis and treatment.

Two commonly available blood tests for Lyme disease are the ELISA and Western blot assay. The ELISA is an inexpensive, widely available, quantitative assay that reflects the magnitude of the antibody response (IgM and IgG) to spirochetal proteins. The Western blot assay (IgM and IgG) is an antibody-based test that detects binding of serum antibodies to an array of 

 antigens; it previously required interpretation by a skilled laboratory technician, but more recent developments have allowed interpretation by optical scanners. The IgG Western blot is considered highly specific for confirmation of current or past infection with 

, while the IgM Western blot is less specific and may result in false positives.

In the 1990s, the CDC recommended a 2-tier testing approach to enhance diagnostic standards (

). The first step involves ordering an ELISA or immunofluorescence assay (an older test that now is less commonly used). If negative results are obtained, no further testing is recommended. If positive or equivocal results are obtained, then the Western blot assay is ordered. A positive result of the Western blot assay supports diagnosis of Lyme disease. A negative result does not necessarily rule it out, as early antibiotic treatment can abrogate the immune response or the assay may have been conducted too early, before the 2 to 3-week interval required for antibody development.

A central problem, therefore, in the 2-tiered method is that sensitivity varies considerably depending upon on how early in the course of infection a patient is tested and on the specific manifestations of 

. Studies suggest that sensitivity of the 2-tier approach in early Lyme disease is poor, and only 29% to 45% of patients with Lyme disease will test positive; many may have false-negative assay results, such as early on in Christina’s case.

 Although sensitivity is excellent for Lyme arthritis, it is lower in disseminated neurologic conditions related to Lyme disease. Equally problematic is that a patient may test positive on an antibody test due to past exposure, and a positive test does not indicate treatment failure. The newer C6 ELISA and VlsE/pepC10 ELISA have improved sensitivity, although they are still far from ideal. In 2019, the CDC updated its recommendation to allow a second enzyme immunoassay, such as the C6 ELISA or VlsE/pepC10 ELISA, to be a reasonable substitute for the Western blot assay.

For suspected neurologic Lyme disease, lumbar puncture is indicated. In central neurologic Lyme disease, CSF analysis typically shows elevated lymphocyte and protein levels with normal glucose levels. Comparing the ratio of antibody levels in the CSF to blood collected on the same day allows determination of the intrathecal index which can provide strong evidence in support of the diagnosis of neurologic Lyme disease. The presence of 

 DNA on polymerase chain reaction testing is also strong evidence for Lyme disease; however, this test has substantial rates of false negatives among patients with neurologic Lyme disease and thus should not be used to disqualify a patient for antibiotic treatment. Structural and functional MRI as well as single-photon emission computed tomography and positron emission tomography scans have been used adjunctively to aid in diagnosis, but they are not sensitive or specific and may be costly or impractical in some clinical settings.

Neuropsychological testing may be helpful in supporting a diagnosis or measuring response to treatment, with studies showing the most consistently identified deficits in adults with Lyme disease to be problems with verbal memory, information processing speed, and memory-related tasks.

 However, this too can be costly and it yields nonspecific results.

Given the limitations of available tests, diagnosis for Lyme disease must be made considering factors such as the patient’s history of tick exposure, time spent in Lyme disease–endemic areas, clinical symptoms, and laboratory findings. Exciting developments are underway in Lyme disease testing, such as urine-based proteomic assays, blood-based metagenomic assays, and point of care tests, that hopefully will improve diagnostic accuracy and reduce delays in the provision of treatment.

Because the diagnosis of Lyme disease is easy to confirm when the erythema migrans rash is present, the research community previously focused its efforts on studying the treatment of early Lyme disease; there have been fewer controlled studies of the later manifestations. Treatment of erythema migrans in adults includes a 10-day course of doxycycline or a 14-day course of cefuroxime or amoxicillin. This results in remission and apparent cure in most cases. Adults with Lyme arthritis can be treated with 28 days of oral doxycycline or amoxicillin. If 

 persist, additional antibiotic therapy is recommended with 2 to 4 weeks of IV ceftriaxone. Acute neurologic Lyme disease (including Lyme-disease associated meningitis, cranial neuropathy, radiculoneuropathy, or other peripheral nervous system manifestations) and Lyme-related heart disease requires 14 to 21 days of IV ceftriaxone, cefotaxime, penicillin G, or oral doxycycline.

 IV antibiotic therapy is preferred for patients hospitalized with Lyme carditis. IV antibiotic therapy is also recommended over oral antibiotics when parenchyma of the brain or spinal cord is involved. The above treatment recommendations are based on the 2020 guidelines created by the IDSA, AAN, and ACR.

 The ILADS treatment guidelines for Lyme disease differ in general by recommending somewhat longer initial courses of antibiotic treatment.

When Lyme-triggered symptoms return or persist despite the standard antibiotic recommendations, considerable controversy arises over how to treat these patients. Approximately 10% to 20% of patients treated for Lyme disease have symptoms that can last for more than 6 months and even years after treatment.

 Common symptoms include muscle and joint pains, brain fog, fatigue, and 

. Such symptoms cause significant distress and functional disability.

There have been 4 controlled studies of repeated antibiotic therapy for patients with PTLDS in the United States. In 2001, Klempner et al conducted 2 studies (1 for Lyme seropositive patients and 1 for seronegative individuals) randomizing patients to either 1 month of IV ceftriaxone followed by 2 months of oral doxycycline or IV placebo followed by oral placebo.

 Ultimately, no difference was found on the self-reported functional disability outcome measure between the antibiotic and placebo groups. The authors also noted that the treatment itself can cause significant risk, such as 

. In 2003, Krupp et al randomized patients with persistent fatigue after treatment of well-documented Lyme disease to either 1 month of IV ceftriaxone or IV placebo, each followed by 5 months of no treatment.

 Those who received ceftriaxone were significantly more likely than those given placebo to be judged as responders on the fatigue measure at 6 months (69% vs 23%, respectively; P < .01). However, somewhat surprisingly, the authors recommended against retreatment, likely due to the risk of serious adverse events associated with IV antibiotics.

In 2008, Fallon et al randomized patients with Lyme encephalopathy to 10 weeks of IV ceftriaxone or placebo.

 There was overall greater cognitive improvement in the drug-treated group that was apparent at 3 months compared with the placebo group (P = .053), but this improvement was not sustained to 6 months. The authors argued that better treatments resulting in sustained cognitive improvement are needed. When the study was reanalyzed using the methods employed by Krupp et al in their fatigue study, very similar significant findings were found—nearly two thirds showed clinically meaningful reduction in fatigue after IV ceftriaxone compared to only 25% on IV placebo. Interpretation of these 4 studies has varied significantly from the IDSA/AAN/ACR guidelines, which largely recommend against retreatment with antibiotics for patients with PTLDS, to ILADS and others who argue retreatment should be considered for debilitating fatigue, as the only randomized controlled trial designed to assess fatigue found significant and clinically meaningful improvement on the primary fatigue outcome measure.

Several hypotheses exist to explain persistent symptoms after treatment for Lyme disease. One hypothesis is that such symptoms may represent an immune response to persistent infection with 

. To date, multiple studies in animals have shown that 

 spirochetes can persist following standard recommended antibiotic treatment of a disseminated infection. Less often, case studies in humans have documented persistent bacteria, though it remains unclear whether these spirochetes are metabolically active or causing clinical disease.

 Other hypotheses include postinfectious processes that result in ongoing immune dysregulation, neural network dysregulation such as central sensitization, and preexisting vulnerability to anxiety and somatization.

 However, the exact cause of persistent symptoms is still not well understood, may be complex and multifactorial, and likely differs depending on the patient. A thorough medical evaluation to rule out tick-borne coinfections such as 

Patients with persistent symptoms after Lyme disease treatment may find that their family, friends, and doctors start to question why they still have symptoms, sometimes leading them to feel hurt, disbelieved, and defensive. Ironically, some of the problems typical of PTLDS may well be “in the head” as a result of neural changes induced by the Lyme disease infection or due to the 

 associated with having a relapsing remitting illness. It is, therefore, important to guide patients in considering a trial of therapeutic strategies and to recognize brain- and symptom-focused treatments (eg, use of a serotonin-norepinephrine reuptake inhibitor for depression and pain, psychotherapy for interpersonal and other issues, graded exercise to address deconditioning, 

 and/or medications to improve sleep) that may have direct healing effects on the body.

There is no specific proven treatment for PTLDS at this time, but many patients find that typical treatments offered by psychiatrists can result in decreased pain, increased energy, better cognition, and enhanced quality of life. Additional research is underway internationally to better understand this complex illness, enhance diagnostic accuracy, and improve treatment outcomes.

Lyme disease is a growing public health problem in the United States. If a sensitive and reliable test of active infection were available, much of the conflict around diagnosis and treatment would be diminished. This is the holy grail that scientists continue to seek. It is important to remember that symptoms of PTLDS (eg, fatigue, head/body aches, sleep difficulties, low mood, irritability, memory problems) can overlap substantially with those of common psychiatric disorders. The treatment approach should be based on the cause—persistent infection, postinfectious factors, or another more likely diagnosis. When psychiatric features are present, the psychiatric care should be optimized to enhance the likelihood of reduced suffering and optimal outcome. As a clinician, you should approach patients with PTLDS or chronic Lyme disease symptoms with humility and compassion, assuming they have been disbelieved by many. Advocate for additional medical workup when appropriate and treat their symptoms with appropriately targeted therapies.

is a fellow in consultation-liaison psychiatry at Columbia University Irving Medical Center with a part-time private practice; she formerly was a chief resident at Columbia’s psychiatry residency program. She is co-author of Conquering Lyme Disease: Science Bridges the Great Divide.

1. Kugeler KJ, Schwartz AM, Delorey MJ, et al. 

Estimating the frequency of Lyme disease diagnoses, United States, 2010-2018.

2. Tickborne diseases of the United States: Lyme disease. Centers for Disease Control and Prevention. Reviewed October 1, 2020. Accessed November 15, 2021. 

https://www.cdc.gov/ticks/tickbornediseases/lyme.html

4. Lantos PM, Rumbaugh J, Bockenstedt LK, et al. 

Clinical practice guidelines by the Infectious Diseases Society of America (IDSA), American Academy of Neurology (AAN), and American College of Rheumatology (ACR): 2020 guidelines for the prevention, diagnosis and treatment of Lyme disease.

Evidence assessments and guideline recommendations in Lyme disease: the clinical management of known tick bites, erythema migrans rashes and persistent disease.

Lyme disease: a neuropsychiatric illness.

7. Fallon BA, Maden T, Erlangsen A, Benros ME. 

Lyme Borreliosis and association with mental disorders and suicidal behavior: a nationwide Danish cohort study.

Neoplasms misdiagnosed as “chronic Lyme disease.”

Conquering Lyme Disease: Science Bridges the Great Divide

Updated CDC recommendation for serologic diagnosis of Lyme disease.

Post-treatment Lyme disease as model of for persistent symptoms in Lyme disease.

Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease.

13. Krupp LB, Hyman LG, Grimson R, et al. 

Study and treatment of post Lyme disease (STOP-LD): a randomized double masked clinical trial.

14. Fallon BA, Keilp JG, Corbera KM, et al. 

A randomized, placebo-controlled trial of repeated IV antibiotic therapy for Lyme encephalopathy.

15. Fallon BA, Petkova E, Keilp JG, Britton CB. 

A Reappraisal of the U.S. Clinical Trials of Post-treatment Lyme Disease Syndrome

Recent progress in Lyme Disease and remaining challenges.

In this CME article, learn more about the controversies surrounding Lyme disease diagnosis and treatment, and common neuropsychiatric presentations of and treatment options.

Lyme Disease in Psychiatry: Controversies, Chronic Symptoms, and Recent Developments

Tales From the Clinic: The Art of Psychiatry

 in a young man who otherwise presents as the perfect patient who is treatment adherent. Individuals with anxiety suffer pervasive impairment in everyday life, and treatment is often not fully effective. Somatic and physical comorbidities typically complicate clinical anxiety presentation, but there are exciting conceptual and treatment considerations in this field worth highlighting, including novel concepts such as gut microbiome influence on anxiety disorders, high body awareness, and somatosensory amplification dimensions.

“Mr West,” aged 30 years, is a well-groomed, soft-spoken man who presents to the clinic for anxiety. He gives you access to extensive medical records spanning the past 8 years, during which time he has received treatment for generalized anxiety. He complains of intense anxiety, fatigue, and hopelessness on a daily basis. According to the patient, his symptoms are comparable with a “living hell on earth.” Mr West had a history of illicit drug use—stimulant use—for a brief period in his early 20s but has not relapsed since. He describes a rich cultural background with life in different countries (accompanying his family as they moved), as well as medications and illicit substance use that are unfamiliar to you, prompting some frantic internet searching. At one point, he mentions fenethylline, which he felt had helped him “fight being tired,” but says he has not used it in about 7 years.

To tackle anxiety symptoms, he has been on a plethora of medications, all of which had adverse effects (AEs) and were discontinued. He has been fully adherent to all treatment recommendations, has never missed any of his appointments, and produces multiple negative urine drug screens. He is diligent in attending all of his psychotherapy sessions as well. Despite his symptoms, he maintains a job, pays his bills with no issues, and dedicates a lot of attention to his ailing mother. However, you note upon history-taking that he has no close friends and has not had romantic involvements, which he attributes to his symptoms: “I’m just not OK, doc, I tell you.” The patient is followed for 6 years.

The first year is spent establishing rapport and getting to know the patient. Monthly visits follow the same pattern: The patient profusely describes beliefs of having “something wrong” that is not properly diagnosed. He asks for brain imaging and cortisol levels, and he brings literature showing sustained brain damage from substance use. Attempts at reassurance often fall flat and are of limited effectiveness, but, as he is a model patient otherwise, you keep trying. Attempts at cognitive behavioral therapy produce limited positive effects, and the patient frequently comments, “This is too simple for me.”

Why are psychotherapeutic interventions crucial in the treatment of GAD and anxiety disorders in general?

Psychosomatics

Delirium: Don’t Miss It

Lyme Disease in Psychiatry: Controversies, Chronic Symptoms, and Recent Developments

My Life is Hell, Doc. Please Help Me!

Care, Concern, and Cautions

Exploring Somatic Symptom Disorder: A Case Report

Case Report Poster: A Smelly Situation

Variant Party

“I’m Not Ready to Die”

Could Childhood ADHD Have Its Roots in Perinatal Autoimmune Disorders?

Treatment of Military Populations