JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Volume 23, Number 10, 2013 ª Mary Ann Liebert, Inc. Pp. 693–696 DOI: 10.1089/cap.2013.23102

Advanced Pediatric Psychopharmacology

Ceftriaxone and Infection in First Episode Adolescent Psychosis Presenters: Mehmet C. Tosyali, MD,1,2 Sanjay Patel, MD,2 Danielle B. Aurora Varas MS, APRN, PMHNP-BC,3 and Eric Alcera, MD1,2 Discussant: Barbara J. Coffey, MD, MS 4

Chief Complaint and Presenting Problem

J

. is a 16-year-old adolescent boy in tenth grade referred to adolescent inpatient service after several months of progressive withdrawal that culminated in marked decrease in speech and activity, and refusal to leave his room. J. was referred from home to a local emergency department by mobile crisis services, and then transferred to an adolescent inpatient unit for admission. History of Present Illness Mother reported an uneventful history, denying recent or past psychiatric symptoms for psychotic, mood, developmental, disruptive behavior, impulse control, and anxiety disorders. Two years prior to admission, at age 14, J. was reported to have been shot in the lower extremity by a stray bullet; this injury resulted in a slow, unsteady, limping gait and chronic foot infection. As a result, J. was absent from school much of the year. Although he went out with his friends occasionally, he was reportedly not as active as he had been in the past. Neither J. nor his mother endorsed mood or posttraumatic anxiety symptoms for that time period. However, J. reported that he could not play basketball because of the injury. In addition, one year prior to admission his 25-year-old brother, who had in utero transmission of HIV, died of AIDS related complications. J. acknowledged he was sad, elaborating no further. Mother, who was HIV positive, reported that she had been increasingly ill beginning around the time of J.’s brother’s death as a result of renal failure, which had required frequent dialysis, clinic visits, and hospitalizations. J. acknowledged worrying about her, especially when she was in the hospital. Her last discharge was two months prior to the beginning of his increasing withdrawal. During her hospitalizations J. stayed with an aunt, where he had to function with a higher level of independence than usual. He was required to take care of various daily needs himself, and take trains to come into the city. His aunt, who seems reliable, reported he was doing well, without decrease in functioning. As J. was not a reliable historian due to psychosis, and his mother provided sparse history, possibly due to her own illness and losses, this was helpful in establishing the beginning of the current syndrome. In this context, mother reported that J. had been acting normally until about four months prior to admission, when one day, without explanation, he stopped attending school. Within a month he was no longer leaving the apartment, and over the last several weeks he

was refusing to leave his room. During this period J. was reported to be withdrawn and less communicative, as he rarely responded to direct questions. He ate and drank when his mother brought him food, but not much. Upon questioning, J. acknowledged hearing voices but would not disclose any details. He denied visual hallucinations, olfactory hallucinations, ideas of reference, and mood and anxiety symptoms. He admitted to smoking marijuana in the past but was unable to provide details. He denied suicidal or homicidal ideation. Past Psychiatric History J. had attended an initial appointment to begin a clinic intake three months prior to admission, which he never completed. He had received no previous psychiatric treatment. Developmental History Mother reported a normal but unplanned pregnancy. As mother was HIV positive, delivery was via planned Caesarean section. Prophylaxis was administered; details are unknown. J. was HIV negative. He was bottle fed, and motor, language, and social developmental milestones were all on time. He was reported to be a pleasant child without any history of behavioral difficulties. Educational History J. was reported to be an average student, receiving B grades in most classes. He had no history of learning difficulties, and his social behavior in school was reported to be appropriate. He was reportedly liked by his teachers. Social History J. lived with his mother in an inner city apartment. His father had died following a myocardial infarction when J. was four years old. As noted above, his older brother had died a year prior to admission. J. was described as a quiet boy who was able to maintain friendships. Family History Mother reported a history of depressed mood, although she had never received treatment. There was no other known family history of psychiatric illness.

1

Adolescent Inpatient Services, Department of Child Adolescent Psychiatry, Bellevue Hospital Center, New York, New York. New York University School Of Medicine, New York, New York. 3 Bellevue Hospital Center, New York, New York. 4 Icahn School of Medicine at Mount Sinai, Department of Psychiatry, New York, New York. 2

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694 Medical History At age 14, J. was shot in the lower extremity by a stray bullet, requiring immediate arterial repair with vascular grafting. He was later diagnosed with incomplete sciatic neuropathy leading to foot drop. He received physical therapy, and according to medical records, was motivated to practice his own exercises to strengthen his leg. But the foot drop and limping gait continued, so J. used a brace. A foot infection began in the form of ulceration six to eight months prior to admission. Antibiotic treatment with amoxicillin-clavulunate was recommended; compliance and results are unknown, though likely both were poor. Physical examination on record one year prior to the injury indicates a healthy, well-nourished boy, Tanner III. Physical examination on record 5 months prior to admission indicates he was active and in summer school making up for missed classes for promotion to the tenth grade, but worried about his mother who was in the hospital at the time. He had no history of substance abuse, including tobacco products and alcohol. He had no environmental or medication allergies and his vaccinations were up to date. Mental Status Exam On admission to the unit J. was a tall, thin, adolescent boy dressed in hospital pajamas. He was somewhat disheveled, and not well groomed. When he walked he favored his healthy foot and walked very slowly, taking more than one second for a single step with either foot. Speech was very limited; he responded to questions with few syllables, left answers incomplete, and at times did not answer at all. J appeared to be cooperative; however, he was easily distracted. Engagement was good at the beginning of the interview, but deteriorated rapidly as the interview progressed. J. described his mood as ‘‘alright.’’ His affect was mostly flat, with inappropriate, out of context smiling and grimacing, which occurred every one to two minutes. When asked about the smiling and laughing, J. would not respond. He denied symptoms of psychosis, though he had admitted to auditory hallucinations to another clinician earlier, without further elaboration. He denied suicidal and homicidal ideation. He had difficulty following instructions and performing tasks he was asked to complete. Cognitive exam attempts were unfruitful, indicative of significant cognitive impairment. He was oriented x4. His current judgment, insight, and speech content were poor. Examination was performed for catatonia with the assistance of a symptom checklist. J. did not exhibit significant rigidity, mannerisms, negativism, waxy flexibility, excitement, immobility, posturing, or other symptoms consistent with catatonia, though he did have rather marked social withdrawal. Physical Examination and Laboratory Tests Physical exam was notable for swelling of a toe with recently drained abscess, and for weakness in the affected lower leg and foot. It was otherwise unremarkable. Infectious disease and podiatry consults were obtained. X-rays of foot suggested possible osteomyelitis. Treatment with amoxicillin-clavulunate 500 mg three times a day was recommended. Vital signs were all stable and within normal limits throughout hospitalization. Anti-nuclear antibodies, syphilis IgG, HIV, Lyme/ Borrelia, hepatitis Ab, and urine toxicology screen were all negative. Brain MRI with and without contrast was normal. Laboratory results were normal except as noted: complete blood count (white blood count, 4.2), sedimentation rate, chemistry panel,

ADVANCED PEDIATRIC PSYCHOPHARMACOLOGY (alkaline phosphatase, 131), ceruloplasmin, vitamin B12, calcium, C-Reactive protein, and hemoglobin A1C (5.6 %). Hospital Course Although reluctant, J.’s mother provided consent to begin treatment with risperidone. He received a single 1 mg oral dose in the emergency room. He was also treated with amoxicillin-clavulunate for the infection in his toe (working diagnosis, osteomyelitis) based on wound culture sensitivity. Though J. verbally agreed to take his medication, he would not do so. He was also difficult to engage in unit activities. Because J. was not adherent to the medication plan, consent for intramuscular injection for treatment of the toe infection was sought on day 6 of hospitalization. Mother agreed to ceftriaxone intramuscular 2 gr/day. The following day J. appeared to be more alert and well groomed, and attended class and activities for the first time. Although still not engaging in spontaneous conversation, he was more verbal, interactive, and appropriate. Differential diagnostic considerations widened at this point to include bipolar disorder and psychosis due to a medical condition, such as cellulitis or osteomyelitis. J. continued to function at this level for the next seven days while continuing daily ceftriaxone. Spontaneous motivation and overall behavior improved. Affect was bright and more appropriate. After seven days ceftriaxone was discontinued and J. was switched to oral amoxicillin-clauvulunate 500 mg three times a day. Aripiprazole 5 mg/day was added, as some inappropriate smiling remained. Three days later, J.’s presenting symptoms recurred. He became less communicative, and complained of auditory hallucinations of demons. Laboratory tests were repeated; hepatitis and Lyme-borrelia titers were obtained and found to be normal. Ammonia (NH4) was mildly elevated at 42.8 (11–35). Liver functions were normal. Lactulose was prescribed for constipation. NH4 was repeated and was found to be within normal range. As catatonia was suspected, J. was given intramuscular lorazepam 2mg, after which he slept for several hours with no change in mental status upon waking. Ten days after discontinuing ceftriaxone and beginning amoxicillinclavulunate and aripiprazole, J. was only slightly improved from his admission mental status. A second seven-day course of ceftriaxone 2 gr/day was administered, as the first seemed to lead to significant benefit. No change in symptoms was noted after two days, so aripiprazole was increased to 10 mg/day. Five days later ceftriaxone was discontinued due to lack of benefit, and aripiprazole was titrated to 20 mg/day. Positive and negative symptoms were significantly improved, and J. was discharged to the day treatment program 38 days after beginning aripiprazole. Toe infection had healed and antibiotic treatment was discontinued 3 days prior to discharge, with scheduled podiatry follow up. Brief Formulation In summary, J. is a 16-year-old adolescent boy with no previous psychiatric history referred for positive and negative symptoms of psychosis that had been increasing for several months. Given a rather sparse history and apparent lack of significant manic or depressive symptoms, the working diagnosis was schizophreniform disorder. However, given the significance of several medical factors, lower extremity injury, and subsequent disability, and what appeared to be chronic osteomyelitis, differential diagnoses also included psychosis secondary to another medical condition, posttraumatic stress disorder, and affective psychosis.

ADVANCED PEDIATRIC PSYCHOPHARMACOLOGY From a biopsychosocial perspective, medical factors were contributory in that J. had experienced an injury to his lower extremity that resulted in a loss of mobility and, eventually, chronic infection. From a psychosocial perspective, J. had experienced several important losses, including his mobility secondary to his lower extremity injury, the recent death of his older brother, and his mother’s chronic illness, all at a critical developmental stage of early adolescence. Multi-Axial Diagnoses Axis I:

Axis II: Axis III: Axis IV: Axis V:

Schizophreniform disorder. Rule out major depression with psychotic features Rule out substance-induced psychotic disorder Rule out post-traumatic stress disorder Rule out psychotic disorder due to another medical condition Deferred Infection of toe Status post, osteomyelitis Significant acute and chronic stressors (gunshot wound, mother’s illness, and death of brother) Current Global Accessment of Functioning score: 20

Discussion This is an interesting and unusual case of medical and psychiatric comorbidity in a 16-year-old adolescent in the early stages of schizophrenia whose psychotic symptoms seemed to decrease with the administration of ceftriaxone. To our knowledge this is the first such report. Ceftriaxone is a beta lactam antibiotic with ability to reach high concentrations in the central nervous system (CNS), and a primary treatment for Lyme neuro-borreliosis (LNB) (Pfister and Rupprecht 2006). There are reports of rapid decrease in LNB psychosis with ceftriaxone treatment (Roelcke et al. 1992; Pfister et al. 1993), though continuing symptoms requiring psychiatric treatment are not uncommon in LNB (Pfister et al. 1991; Ljøstad and Mygland 2010; Markeljevic et al. 2011). Similar to this case, one study in patients with post-treatment Lyme encephalopathy reported that ceftriaxone therapy resulted in cognitive improvement, with relapse after the antibiotic was discontinued (Fallon et al. 2008). The authors suggest infection-independent actions of ceftriaxone as a possible explanation. Indeed ceftriaxone may have several such actions. There is growing evidence that certain antibiotics have significant immunomodulatory effects (Tauber and Nau 2008). Initial studies showed no effect of ceftriaxone on in vitro phagocyte T cell function, or cytokine production (Gialdroni et al. 1984; Pacheco et al. 1994; Meloni et al. 1995) and no change in neutrophil or phagocyte function, peripheral WBC, serum immunoglobulins, or lymphocyte subpopulation in humans (Gialdroni et al. 1984; Karakaya et al. 1995). However, recent studies indicate significant immunomodulatory effects of ceftriaxone, including in vitro increase in phagocyte and T cell chemotaxis, attenuation of cyclophosphamide induced suppression of lymphoproliferation, protection of neurons against apoptotic death induced by ionizing radiation, and reduced levels of pro-inflammatory cytokines IFN-gamma, TNF-alpha, matrix metallo-proteinase (MMP)-9, activated caspase-9, IL-17, decreased antigen presentation to and reduced migration of T cells (Gialdroni et al. 1984; Jimenez-Valera et al. 2003; Tikka 2001; Brooks et al. 2005; Chu et al. 2007; Melzer et al. 2008).

695 In addition, as a broad spectrum antibiotic at concentrations used for typical antibacterial therapy, ceftriaxone has the ability to significantly alter the gut microbiome, leading to change in the fecal metabolome and potentially effecting T-cell populations, their subpopulations in Peyer’s patches, and expression of various cytokines (Aminov 2013). Similarly, an association between inflammatory abnormalities and schizophrenia has been found repeatedly (Hornig 2013; Kirkpatrick and Miller 2013; Zakharyan and Boyajyan 2013). Immunoinflammatory mechanisms associated with microglial activation have been gaining interest, as have the importance of adjunctive anti-inflammatory treatments such as minocycline, a tetracycline antibiotic with important anti-inflammatory effect, and aspirin, a COX-1 and COX-2 inhibitor (Debnath and Venkatasubramanian 2013; Kelly et al. 2011; Chaudry et al. 2012; Berk et al. 2013) Finally, sickness behavior, with some phenomenology similar to negative symptoms, may be related to inflammatory activity (Maes et al. 2012; Moon et al. 2011). If J.’s infection had led to increased inflammation that contributed to his psychotic symptoms, it is possible that ceftriaxone may have led to decrease in psychosis through modulation of inflammatory factors. An additional effect of ceftriaxone is its ability to modulate expression of the glutamate transporter GLT1/EAAT2 via gene activation (Rothstein et al. 2005). Primarily expressed in astroglial cells, EAAT2 is responsible for 90% of glutamate uptake, and its activation leads to protection from glutamate excitotoxicity (Danbolt 2001). The excitotoxic hypothesis of schizophrenia suggests that in a subset of patients with schizophrenia, progressive excitotoxic neuronal cell death in hippocampal and cortical areas occurs via disinhibition of glutamatergic projections to these areas. Patients who have excitotoxicity would have pronounced negative symptoms and cognitive deficits, and profound psychosocial deterioration (Deutsch et al. 2001). J. had a similar presentation, with pronounced negative symptoms and withdrawal. Activation of the glutamate transporter may have led to decrease in toxicity and, therefore, symptoms. It is also interesting that a second course of ceftriaxone that followed the introduction of aripiprazole by a week was not beneficial for J.’s psychotic symptoms. Notably, aripiprazole also has anti-inflammatory properties and is capable of reducing microglial inflammatory reactions in vitro (Kato et al. 2008). If ceftriaxone first led to improvement of psychosis through anti-inflammatory effects, followed by another week on aripiprazole with additional anti-inflammatory effect, inflammation could have already decreased to an extent that ceftriaxone was no longer needed. A final note of interest: aripiprazole is capable of suppressing expression of excitatory amino acid transporter (EAAT2) (Segnitz et al. 2009). In theory, it could be possible that aripiprazole suppressed EAAT2 to the extent that ceftriaxone was no longer able to increase its activity. If so, the initial improvement on ceftriaxone may indeed have failed on the second round in association with aripiprazole. Disclosures Drs. Tosyali and Alcera and Ms. Varas have no conflicts of interest or financial ties to disclose. Dr. Patel received funding from Eli Lilly through the American Academy of Child and Adolescent Psychiatry Educational Outreach Program, to attend their October, 2011 Annual Meeting. Dr. Coffey has received research support from Eli Lilly Pharmaceutical, NIMH, NINDS, Tourette Syndrome

696 Association, Otsuka, Shire, Bristol-Myers Squibb, Pfizer, and Boehringer Ingelheim. Acknowledgment We would like to acknowledge and thank Dr. Jennifer Havens, Dr. Donald Goff, Dr. Donald Klein, Dr. Dolores Malaspina, and Dr. Peter Weiden for listening, discussing, and trying to point us in the right direction, and Laura Ibanez Gomez and Zoey Shaw for their assistance in review and preparation of the manuscript. References Aminov RI: Biotic acts of antibiotics. Front Microbiol 19:241, 2013. Berk M, Dean O, Drexhage H, McNeil JJ, Moylan S, O’Neil A, Davey CG, Sanna L, Maes M: Aspirin: A review of its neurobiological properties and therapeutic potential for mental illness. BMC Med 11:74, 2013. Brooks BM, Hart CA, Coleman JW: Differential effects of betalactams on human IFN-gamma activity. J Antimicrob Chemother 56:1122–1125, 2005. Chaudhry IB, Hallak J, Husain N, Minhas F, Stirling J, Richardson P, Dursun S, Dunn G, Deakin B: Minocycline benefits negative symptoms in early schizophrenia: A randomised double-blind placebo-controlled clinical trial in patients on standard treatment. J Psychopharmacol 26:1185–1193, 2012. Chu K, Lee ST, Sinn DI, Ko SY, Kim EH, Kim JM, Kim SJ, Park DK, Jung KH, Song EC, Lee SK, Kim M, Roh JK: Pharmacological induction of ischemic tolerance by glutamate transporter-1 (EAAT2) upregulation. Stroke 38:177–182, 2007. Danbolt NC. Glutamate uptake. Prog Neurobiol 65:1–105, 2001. Debnath M, Venkatasubramanian G: Recent advances in psychoneuroimmunology relevant to schizophrenia therapeutics. Curr Opin Psychiatry 26:433–439, 2013. Deutsch SI, Rosse RB, Schwartz BL, Mastropaolo J.A Revised excitotoxic hypothesis of schizophrenia: therapeutic implications. Clin Neuropharmacol 24:43–49, 2001. Fallon BA, Keilp JG, Corbera KM, Petkova E, Britton CB, Dwyer E, Slavov I, Cheng J, Dobkin J, Nelson DR, Sackeim HA. A randomized, placebo-controlled trial of repeated IV antibiotic therapy for Lyme encephalopathy. Neurology 70:992–1003, 2008. Gialdroni Grassi G, Fieta A, Sacchi F, Derose V: Influence of ceftriaxone on natural defense systems. Am J Med 77(4C):37–41, 1984. Hornig M: The role of microbes and autoimmunity in the pathogenesis of neuropsychiatric illness. Curr Opin Rheumatol 25:488–795, 2013. Karakaya A, Gu¨mu¨xay s S, Yu¨cesoy B, Hengirmen S. Effect of shortterm therapy with ceftizoxime and ceftriaxone on human peripheral WBC, serum immunoglobulins and lymphocyte subpopulations. Immunopharmacol Immunotoxicol 17:775–781, 1995. Kato T, Mizoguchi Y, Monji A, Horikawa H, Suzuki SO, Seki Y, Iwaki T, Hashioka S, Kanba S: Inhibitory effects of aripiprazole on interferon-gamma-induced microglial activation via intracellular Ca2 + regulation in vitro. J. Neurochem 105:815–825, 2008. Kelly DL, Vyas G, Richardson CM, Koola M, McMahon RP, Buchanan RW, Wehring HJ: Adjunct minocycline to clozapine treated patients with persistent schizophrenia symptoms. Schizophr Res 133(1–3):257–258; 2011. Kirkpatrick B, Miller BJ: Inflammation and schizophrenia. Schizophrenic Bull. Epub ahead of print Sep 26, 2013. Jimenez-Valera M, Moreno E, Angeles Amat M, Ruiz-Bravo A: Modification of mitogen-driven lymphoproliferation by ceftriaxone in normal and immunocompromised mice. Int J Antimicrobial Agents 22:607–612, 2003.

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Address correspondence to: Barbara J. Coffey, MD, MS Ichan School of Medicine at Mount Sinai One Gustave L. Levy Place, Box 1230 New York, NY 10029 E-mail: [email protected]

Ceftriaxone and infection in first episode adolescent psychosis.

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