Table 1. Summary Table of the Included Articles.

LSLD, long-standing Lyme disease; ELISA, enzyme-linked immunosorbent assay; CSF, cerebrospinal fluid; MMSE, Mini-Mental State Examination; CDT, clock drawing test

Reference	Country	Study Objectives/Aims	Study Design	Sampling Data/Collection Methods	Sample	Key Findings	Limitations
Bransfield (2017) [11]	United States	To investigate the association between suicide, Lyme, and associated diseases	Retrospective study: clinical chart review of patients with Lyme-associated diseases (LAD). Measured prevalence of suicidal and homicidal tendencies among these patients	Randomly selected inactive patient charts with LAD from the author’s practice were analyzed. Four groups based upon symptoms were made: suicidal and homicidal, suicidal not homicidal, experiencing explosive anger not suicidal or homicidal, and not suicidal, homicidal, or experiencing explosive anger	Two hundred fifty-three patients with LAD (58% female, 42% male, ages 8-64 years, and average age of 39 years). Clinical or serological Lyme disease (LD) diagnosis	Participants were infected an average of eight years before diagnosis and antibiotic treatment, demonstrating a delayed diagnosis. Forty-three percent had suicidal tendencies. Twenty-six percent of these suicidal patients were also homicidal. However, there were no patients who were homicidal without also being suicidal	The chart review included patients who did not meet the CDC criteria-based definition for LD (two-tier testing). Researchers calculated the rate of suicide based on a CDC calculator and patient symptoms. Patients who were co-infected with other viruses were included
Hündersen et al. (2021) [12]	Germany	To examine the relationship between neuropsychiatric and psychological symptoms in patients with Lyme borreliosis (LB)	Online questionnaire via survey software (Unipark, Tivia, New York, NY). Observational cross-sectional study February-April 2020. Compared experimental group (LD patients) to a control group	Researchers collected data from both the experimental group and control group via an online questionnaire that was shared via social media (Facebook) and flyers in medical facilities and through the test person system of the Medical School of Hamburg. The questionnaire assessed the individuals’ quality of life, sleep quality, attention, depressive symptoms, memory, and careers	The experimental group (history of LD): 189 females, 62 males, and one non-binary, average age of 51 years (range: 19-84 years); control group: 211 females and 56 males, average age of 27 years (range: 18-70 years)	Lyme disease patients often wait an average of eight years and see an average of eight physicians before a final diagnosis is made. Less than half the subjects (46%) received their diagnosis within the first five years after the development of symptoms. Results showed that LD can cause limitations in the quality of life, sleep, attention, memory, and depressive symptoms. Statistically significant differences were observed in the prevalence and severity of these symptoms when compared to the control group	Data were self-reported. One diagnostic test included in the questionnaire for diagnosing LD was lymphocyte transformation test (LTT), which is not recommended due to its low specificity
Makara-Studzinska et al. (2017) [13]	Poland	To evaluate the symptoms of depression and anxiety associated with fibromyalgia and erythema migrans (EM) in Borrelia burgdorferi infection	Case-by-case study. Measured levels of anxiety and depressive symptoms among patients diagnosed with B. burgdorferi infection who also reported symptoms associated with fibromyalgia. Questionnaires and serological tests were used to gather data	A group of 87 patients with clinically and serologically diagnosed B. burgdorferi (mean age of 53.37) was formed. Subjects were examined using the State-Trait Anxiety Inventory, Beck Depression Inventory (BDI), various immunological tests, and tests for fibromyalgia	Eighty-seven participants (43 females and 44 males) diagnosed and treated for B. burgdorferi infection who also presented with symptoms of fibromyalgia	Patients with early B. burgdorferi infection also diagnosed with fibromyalgia showed the highest levels of anxiety and depression. The results showed that serological markers of infection could act as indicators of depression level in patients with B. burgdorferi infection. Patients with IgM- and IgG+ serological markers, showing more advanced infection, had the lowest levels of anxiety and depressive symptoms	All patients were ethnically white Europeans. The sample size of this study is small, and other studies have shown that IgG antibody levels do not differ between healthy and infected people in regard to depression symptoms
Bransfield (2018) [14]	United States	To examine the association between aggressiveness, homicidality, homicide, and LD	Retrospective study design, measured aggressive behaviors before and after LD diagnosis compared to a control group via clinical chart reviews	Patient charts were reviewed and analyzed. Fifty patients with previous homicidal history and 50 patients with no homicidal history were included. Aggressive behavior rate was compared before LD infection to after within each group	One hundred total charts reviewed (50 homicidal and 50 non-homicidal LD patients); 52% male and 48% female	Of the LD patients, 9.6% were homicidal with an average diagnosis delay of nine years. Most aggression in LD patients was impulsive, usually provoked by intrusive symptoms, sensory stimulation, or frustration	The first chart review conducted included 1,000 charts from LD patients, and 50 were reported to show homicidal tendencies
Schmidt et al. (2015) [15]	Germany	To determine the frequency and extent of changes in cognitive function in patients with neuroborreliosis (NB)	Case-controlled study; measured brain atrophy and cognitive decline using clinical workups and questionnaires	Sixty patients were given neurological and neuropsychological workups six months or longer after treatment for proven NB. Standardized neurological examinations quantified with the Scripps Neurological Rating Scale (SNRS) were used to assess cognitive function. The results were compared to a group of 30 healthy controls who tested negative for B. burgdorferi	Sixty patients with neuroborreliosis between ages 15 and 70 at the time of treatment. Thirty patients who tested negative for B. burgdorferi	Patients in the NB group showed lower scores on the SNRS and lower performance in frontal executive functions compared to the healthy control group. Cognitive sum scores were also lower in the NB group compared to the control group. There were no significant differences found for health quality of life, sleep disturbance, psychiatric symptom load, or brain atrophy	No major limitations noted
Bransfield et al. (2020) [16]	United States	To describe the clinical presentation of Lyme borreliosis patients with chronic, late-stage psychiatric symptoms from a review of 100 charts and to develop a clinical assessment system from these findings	Observational retrospective cohort study. Questionnaire used to compare patient’s symptoms pre-infection and post infection	The first author developed the assessment form used in this study to evaluate patients with late-stage LD. The same assessment was performed on all patients by the first author. The date of infection was also established from each chart	One hundred patients enrolled; the average age was 38 years (range: 6-89 years)	Out of 100 patients enrolled, 70 had a delayed diagnosis and treatment, with the average delay being nine years. The prevalence of each clinical finding pre-infection and post infection was compared and calculated within the 95% confidence interval. The average patient had five symptoms pre-infection and 82 post infection	The patient’s neuropsychiatric status before infection was approximated based on recall
Keilp et al. (2019) [17]	United States	Patients with post-treatment Lyme disease syndrome (PTLDS) were compared to patients with major depressive disorder (MDD), as well as healthy comparison subjects, to see if there were significant differences in cognitive function between the two groups	Cohort study; measured cognition, including memory in patients with MDD and PTLDS via clinical workups and questionnaires	Performance on Wechsler Adult Intelligence Scale-III (WAIS-III) and Wechsler Memory Scale-III (WMS-III) on subgroups of PTLDS, MDD, and healthy controls	Ninety-seven healthy controls (average age of 38.3); 81 PTLDS (average age of 47.8); 92 MDD (average age of 38.9)	Most patients in the PTLDS group had a relatively late diagnosis after initial symptom onset, thus leading to a relatively long period of illness before initial treatment. Although mean scores on most WAIS-III and WMS-III tests in the PTLDS group did not fall outside of the “average” range, they reflect consistently lower performance on measures of working memory, learning, and information retrieval in a sample with above-average ability. BDI scores in LSLD patients were statistically higher than those found in the healthy population but lower than those diagnosed with MDD	No major limitations noted
Oczko-Grzesik et al. (2017) [18]	Poland	To assess the functional status of patients with borreliosis and NB in relation to the frequency of the occurrence of cognitive deficits, depression, and anxiety disorders	Cross-sectional study, 2005-2012. Compared patients with Lyme arthritis and Lyme NB through clinical workups, interviews, and laboratory testing. The outcome measures included cognitive functioning and affective functioning	Data was collected from patients hospitalized at the Department of Infectious Diseases, Specialistic Hospital No. 1, in Bytom, Poland, between 2005 and 2012. The data collection methods included a standardized interview, clinical examination, laboratory tests (ELISA, western blot, and CSF), and psychological testing (MMSE, CDT, and BDI)	One hundred twenty-one patients (61 females and 60 males), ages 18-65 (average 40 years), who were diagnosed with late-stage LD (mean duration of 2.5 years). There were 46 patients (31 females and 15 males) with Lyme arthritis and 75 patients (30 females and 45 male) with Lyme NB	In patients with LD, particularly in those with NB, an increased frequency of depressive and neurotic disorders was observed. Neurotic disorders, mainly adaptive, are most common in males with LD, while depressive disorders were more frequent in females. In patients with NB, particularly in females, an increased frequency of cognitive deficits was observed. After antibiotic therapy, the prevalence of depression, anxiety, and mild cognitive disorders decreased in patients with Lyme arthritis and NB	No major limitations noted
Geebelen et al. (2022) [19]	Belgium	To compare nonspecific symptoms between Lyme borreliosis (LB) patients and a non-LB control at six- and 12-month follow-up; to estimate the proportion of PTLDS in two groups of LB patients: patients with erythema migrans (EM) and disseminated or late LB	Prospective cohort study, from June 2016 to December 2019. Compared nonspecific symptoms among patients diagnosed with EM to disseminated/late LB and to a non-LB control group using questionnaires	LB patients were asked to fill in a questionnaire at diagnosis at one, three, and six months (12 and 24 months if possible) post treatment. These questionnaires were also completed by the control group at the time of inclusion, six months after inclusion, and 12 months after inclusion	Participants were 18 years or older; 120 patients with EM (46 males and 74 females); 15 patients with disseminated/late LB (13 males and two females); 128 healthy control patients (46 males and 82 females)	The proportion of PTLDS patients were found to be 5.9% (95% CI: 2.7-12.9) in EM patients and 20.9% (95% CI: 6.8-64.4) in disseminated/late LB patients. The chance of receiving a PTLDS diagnosis was found to be significantly higher in patients with late or disseminated LB	Predefined sample sizes could not be included; small sample size for the disseminated/late LB group; the disseminated/late LB group was heavily skewed toward males
Rebman et al. (2017) [20]	United States	To delineate PTLDS-specific patterns in physical examination findings, clinical laboratory results, symptom reporting, and quality of life. These patterns would then be compared to control participants with no prior history of LD	Case series style: outcome measures were the quality of life based on a 36-item symptom list. Patients were evaluated through clinical workups and questionnaires	The participants with PTLDS were physician- or self-referred to the Johns Hopkins Lyme Disease Research Center. A clinical, laboratory evaluation and a quality of life analysis were conducted on the patients. Symptoms were measured by standardized questionnaires including the Fatigue Severity Scale (FSS), the short-form McGill Pain Questionnaire (SF-MPQ), and the BDI	Sixty-one participants met the criteria for PTLDS (52.5% female, 93.4% white and non-Hispanic); 26 participants had no prior history of LD or PTLDS and served as healthy controls (53.9% female, 88.5% white and non-Hispanic)	Initial delayed or misdiagnosis was characterized in 59% of the participants with PTLDS. Patients in the PTLDS group were highly symptomatic, with poor health-related quality of life. PTLDS patients exhibited higher levels of fatigue, musculoskeletal pain, sleep disturbance, and depression compared to the healthy control group	No major limitations noted