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Evidence-based guidelines for the management of Lyme disease. BIBLIOGRAPHIC SOURCE(S)
Evidence-based guidelines for the management of Lyme disease. Expert Rev Anti Infect Ther 2004;2(1 Suppl):S1-13. [66references]
This is the current release of the guideline. ** REGULATORY ALERT ** FDA WARNING/REGULATORY ALERT Note from the National Guideline Clearinghouse: This guideline references a drug(s) for which important revised regulatory and/or warning information has been released.
: Roche informed healthcare professionals about revisions made to theprescribing information for Rocephin to clarify the potential risk associated with concomitant use of Rocephin with calcium orcalcium-containing solutions or products. : Update to the existing black box warning on the prescribing information on alantidepressant medications to include warnings about the increased risks of suicidal thinking and behavior in young adults ages18 to 24 years old during the first one to two months of treatment. BRIEF SUMMARY CONTENT RECOMMENDATIONS MAJOR RECOMMENDATIONS Highlights of Guidelines
Since there is currently no definitive test for Lyme disease, laboratory results should not be used to exclude an individual fromtreatment. Lyme disease is a clinical diagnosis and tests should be used to support rather than supersede the physician’s judgment. The early use of antibiotics can prevent persistent, recurrent, and refractory Lyme disease. The duration of therapy should be guided by clinical response, rather than by an arbitrary (i.e., 30 day) treatment course. The practice of stopping antibiotics to al ow for delayed recovery is not recommended for persistent Lyme disease. In thesecases, it is reasonable to continue treatment for several months after clinical and laboratory abnormalities have begun to resolveand symptoms have disappeared. Diagnostic Concerns
The most important method for preventing chronic Lyme disease is recognition of the early manifestations of the disease.
Early Lyme disease classical y presents with a single erythema migrans (EM or "bul ’s-eye") rash. The EM rash may be absent in over50% of Lyme disease cases, however. Patients should be made aware of the significance of a range of rashes beyond the classicEM, including multiple, flat, raised, or blistering rashes. Central clearing was absent in over half of a series of EM rashes. Rashes canalso mimic other common presentations including a spider bite, ringworm, or cel ulitis.
Physicians should be aware that fewer than 50% of al Lyme disease patients recal a tick bite. Early Lyme disease should also beconsidered in an evaluation of "off-season" onset when flu-like symptoms, fever, and chil s occur in the summer and fal . Earlyrecognition of atypical early Lyme disease presentation is most likely to occur when the patient has been educated on this topic. New Chronic Lyme Disease Presentations
A detailed history may be helpful for suggesting a diagnosis of chronic Lyme disease. Headache, stiff neck, sleep disturbance, andproblems with memory and concentration are findings frequently associated with neurologic Lyme disease. Other clues to Lymedisease have been identified, although these have not been consistently present in each patient: numbness and tingling, muscletwitching, photosensitivity, hyperacusis, tinnitus, lightheadedness, and depression.
Most patients diagnosed with chronic Lyme disease have an indolent onset and variable course. Neurologic and rheumatologicsymptoms are characteristic, and increased severity of symptoms on wakening is common. Neuropsychiatric symptoms alone aremore often seen in chronic than acute Lyme disease. Although many studies have found that such clinical features are often not uniqueto Lyme disease, the striking association of musculoskeletal and neuropsychiatric symptoms, the variability of these symptoms, andtheir recurrent nature may support a diagnosis of the disease. The Limitations of Physical Findings
A comprehensive physical examination should be performed, with special attention to neurologic, rheumatologic, and cardiacsymptoms associated with Lyme disease.
Physical findings are nonspecific and often normal, but arthritis, meningitis, and Bel ’s palsy may sometimes be noted. Available datasuggest that objective evidence alone is inadequate to make treatment decisions, because a significant number of chronic Lymedisease cases may occur in symptomatic patients without objective features on examination or confirmatory laboratory testing.
Factors other than physical findings, such as a history of potential exposure, known tick bites, rashes, or symptoms consistent with thetypical multisystem presentation of Lyme disease, must also be considered in determining whether an individual patient is a candidatefor antibiotic therapy. Sensitivity Limitations of Testing
Treatment decisions should not be based routinely or exclusively on laboratory findings. The two-tier diagnostic criteria, requiring botha positive enzyme-linked immunosorbent assay (ELISA) and western blot, lacks sensitivity and leaves a significant number ofindividuals with Lyme disease undiagnosed and untreated. These diagnostic criteria were intended to improve the specificity of teststo aid in identifying wel -defined Lyme disease cases for research studies. Though arbitrarily chosen, these criteria have been used asrigid diagnostic benchmarks that have prevented individuals with Lyme disease from obtaining treatment. Diagnosis of Lyme diseaseby two-tier confirmation fails to detect up to 90% of cases and does not distinguish between acute, chronic, or resolved infection.
The Centers for Disease Control and Prevention (CDC) considers a western blot positive if at least 5 of 10 immunoglobulin G (IgG)bands or 2 of 3 immunoglobulin M (IgM) bands are positive. However, other definitions for western blot confirmation have beenproposed to improve the test sensitivity. In fact, several studies showed that sensitivity and specificity for both the IgM and IgG westernblot range from 92 to 96% when only two specific bands are positive.
Lumbar puncture has also been disappointing as a diagnostic test to rule out concomitant central nervous system infection. In Lymedisease, evaluation of cerebrospinal fluid is unreliable for a diagnosis of encephalopathy and neuropathy because of poor sensitivity. For example, pleocytosis was present in only one of 27 patients (sensitivity 3%) and with only seven cel s. The antibody index waspositive (>1) in only one of 27 patients (sensitivity 3%). An index is the ratio between Lyme ELISA antibodies in the spinal fluid andLyme ELISA antibodies in the serum. The proposed index of 1.3 would be expected to have even worse sensitivity.
Several additional tests for Lyme disease have been evaluated. These include antigen capture, urine antigen, and polymerase chainreaction. Each has advantages and disadvantages in terms of convenience, cost, assay standardization, availability, and reliability. These tests remain an option to identify people at high risk for persistent, recurrent, and refractory Lyme disease but have not beenstandardized.
A patient who has tested seronegative may have a clinical presentation consistent with Lyme disease, especial y if there is noevidence to indicate another il ness.
Although many individuals do not have confirmatory serologic tests, surveil ance studies show that these patients may have a similarrisk of developing persistent, recurrent, and refractory Lyme disease compared with the seropositive population. Continued Importance of Differential Diagnosis
The differential diagnosis of Lyme disease requires consideration of both infectious and noninfectious etiologies. Amongnoninfectious causes are thyroid disease, degenerative arthritis, metabolic disorders (vitamin B12 deficiency, diabetes), heavy metaltoxicity, vasculitis, and primary psychiatric disorders.
Infectious causes can mimic certain aspects of the typical multisystem il ness seen in chronic Lyme disease. These include viralsyndromes, such as parvovirus B19 or West Nile virus infection, and bacterial mimics, such as relapsing fever, syphilis, leptospirosis,and mycoplasma.
The clinical features of chronic Lyme disease can be indistinguishable from fibromyalgia and chronic fatigue syndrome. Theseil nesses must be closely scrutinized for the possibility of etiological Borrelia burgdorferi infection.
Clinical judgment remains necessary in the diagnosis of late Lyme disease. A problem in some studies that relied on objectiveevidence was that treatment occurred too late, leaving the patient at risk for persistent and refractory Lyme disease.
As noted, time-honored beliefs in objective findings and two-tier serologic testing have not withstood close scrutiny. Lyme diseaseshould be suspected in patients with newly acquired or chronic symptoms (headaches, memory and concentration problems, and jointpain). Management of patients diagnosed on the basis of clinical judgment needs to be tested further in prospective trials, anddiagnostic reproducibility must be verified.
Polymicrobial infection is a new concern for individuals with Lyme disease, and coinfection is increasingly reported in critical y ilindividuals. Although B. burgdorferi remains the most common pathogen in tick-borne il nesses, coinfections including Ehrlichia andBabesia strains are increasingly noted in patients with Lyme disease, particularly in those with chronic il ness. Bartonella is anotherorganism that is carried by the same ticks that are infected with B. burgdorferi, and evidence suggests that it is a potential coinfectingagent in Lyme disease.
Recent animal and human studies suggest that Lyme disease may be more severe and resistant to therapy in coinfected patients. Thus, concurrent testing and treatment for coinfection is mandatory in Lyme disease patients. Treatment Considerations
Since Lyme disease can become persistent, recurrent, and refractory even in the face of antibiotic therapy, evaluation and treatmentmust be prompt and aggressive.
Although no wel designed studies have been carried out, the available data support the prompt use of antibiotics to prevent chronicLyme disease. Antibiotic therapy may need to be initiated upon suspicion of the diagnosis, even without definitive proof. Neither theoptimal antibiotic dose nor the duration of therapy has been standardized, but limited data suggest a benefit from increased dosagesand longer treatment, comparable to the data on tuberculosis and leprosy which are caused by similarly slow-growing pathogens.
In acute Lyme disease, the choice of antibiotics should be tailored to the individual and take into account the severity of the diseaseas wel as the patient’s age, ability to tolerate side effects, clinical features, al ergy profile, comorbidities, prior exposure,epidemiologic setting, and cost.
Conversely, persistent and refractory Lyme disease treatment is more likely to include intravenous and/or intramuscular antibiotics. The choices depend in part on the patient’s response to antibiotic therapy and on the success of antibiotics in treating other Lymedisease patients.
Therapy usual y starts with oral antibiotics, and some experts recommend high dosages. The choice of antibiotic therapy is guided byweighing the greater activity of intravenous antibiotics in the central nervous system against the lower cost and easy administration oforal antibiotics for B. burgdorferi.
For many Lyme disease patients, there is no clear advantage of parenteral therapy. Along with cost considerations and pressure totreat patients with Lyme disease with the least intervention, there is growing interest in the use of oral therapy.
First-line drug therapies for Lyme disease may include (in alphabetical order): oral amoxicil in, azithromycin, cefuroxime,clarithromycin, doxycycline, and tetracycline. These antibiotics have similar favorable results in comparative trials of early Lymedisease.
It is common practice to consider intravenous antibiotics upon failure of oral medications in patients with persistent, recurrent, orrefractory Lyme disease, and as the first line of therapy for certain conditions, (i.e., encephalitis, meningitis, optic neuritis, jointeffusions, and heart block).
Ideal y, the intravenous antibiotic should be selected on the basis of in vitro sensitivity testing or clinical experience. Intravenousantibiotics are also justified by concern for penetration into the central nervous system.
Until recently, ceftriaxone, cefotaxime, and penicil in were the only intravenous antibiotics routinely studied for use in Lyme disease. Intravenous imipenem, azithromycin, and doxycycline have an adequate antispirochetal spectrum of activity and may representsuitable alternative therapies. However, the latter two drugs are often considered for intravenous use only if they are not toleratedoral y.
Intramuscular benzathine penicil in (1.2 to 2.4 mil ion units per week) is sometimes effective in patients who do not respond to oral andintravenous antibiotics. If intramuscular benzathine penicil in is used, long-term therapy may be necessary due to the low serumconcentration of this form of penicil in. Benzathine penicil in has mainly been used in patients who have had multiple relapses whilereceiving oral or intravenous antibiotic therapy or who are intolerant of oral or intravenous antibiotics.
Combination therapy with two or more antibiotics is now increasingly used for refractory Lyme disease and has also been given asinitial therapy for some chronic presentations.
This approach is already used for another tick-borne il ness, babesiosis. Oral amoxicil in, cefuroxime, or (more recently) cefdinircombined with a macrolide (azithromycin or clarithromycin) are examples of combination regimens that have proven successful inclinical practice, although control ed clinical trials are lacking in persistent, recurrent, and refractory Lyme disease.
Combination therapy in patients with Lyme disease raises the risk of adverse events. This risk must be weighed against the improvedresponse to combination therapy in Lyme disease patients failing single agents.
Clinicians increasingly use the sequence of an intravenous antibiotic fol owed by an oral or intramuscular antibiotic. In two recent caseseries that employed combination therapy and sequential therapy, most patients were successful y treated. A logical and attractivesequence would be to use intravenous therapy first (e.g., intravenous ceftriaxone), at least until disease progression is arrested andthen fol ow with oral therapy for persistent and recurrent Lyme disease.
Increasingly, clinicians recommend that certain drugs used for Lyme disease be given at higher daily doses: for example, 3,000–6,000 mg of amoxicil in, 300–400 mg doxycycline, and 500–600 mg of azithromycin. Some clinicians prescribe antibiotics usingblood levels to guide higher doses. Close monitoring of complete blood counts and chemistries are also required with this approach.
With higher doses, there may be an increase in adverse events in general and gastrointestinal problems in particular. Acidophilus hasreportedly reduced the incidence of Clostridium difficile colitis and non-C. difficile antibiotic-related diarrhea.
Serious adverse effects of antibiotics, however, were less common than previous estimates. In a recent clinical trial of chronic Lymedisease, the overal serious adverse event rate was 3% after three months of antibiotics, including 1 month of intravenous antibiotics. Clinicians who have experience with higher dose antibiotic therapy must balance the benefit of higher drug levels achieved with thistherapy against the modest risk of gastrointestinal and other side effects.
Because of the disappointing long-term outcome with shorter courses of antibiotics, the practice of stopping antibiotics to al ow for adelayed recovery is no longer recommended for patients with persistent, recurrent, and refractory Lyme disease. Reports show failurerates of 30–62% within 3 years of short-course treatment using antibiotics thought to be effective for Lyme disease. Conversely forneurologic complications of Lyme disease, doubling the length of intravenous ceftriaxone treatment from 2 to 4 weeks improved thesuccess rate from 66 to 80%.
The management of chronic Lyme disease must be individualized, since patients wil vary according to severity of presentation andresponse to previous treatment.
Concurrent risk factors (i.e., coinfections, previous treatment failures, frequent relapses, neurologic involvement, or previous use ofcorticosteroids) or evidence of unusual y severe Lyme disease should lead to the initiation of prolonged and/or intravenous antibiotictreatment. Physicians should always assess the patient’s response to treatment before deciding on appropriate duration of therapy(i.e., weeks versus months).
The importance of establishing the diagnosis of Lyme disease is heightened in light of increasing concern about antibiotic overuse. After an appropriate history, physical examination, and laboratory testing are completed, empiric antimicrobial therapy should beinitiated on the basis of clinical clues, the severity of the patient’s acute il ness, underlying disease, and the likelihood of B. burgdorferiinfection. The International Lyme and Associated Diseases Society (ILADS) working group recommends that empiric treatment beconsidered routine for patients with a likely diagnosis of Lyme disease.
Persistent Lyme disease is more resistant to treatment and more likely to produce a relapse. Although persistent Lyme disease mayresolve without additional therapy, many experts believe that this condition should be treated with repeated and prolonged antibiotics. Physicians should extend the duration of antibiotics to prevent or delay recurrent and refractory Lyme disease.
Despite previous antibiotic treatment, Lyme disease has a propensity for relapse and requires careful fol ow-up for years. The datasuggest that failure to eradicate the organism may be the reason for a recurrence of symptoms. Early and aggressive treatment withantibiotics is indicated for recurrent Lyme disease. The ultimate impact from retreating each episode of recurrent Lyme disease iscurrently unclear.
Refractory Lyme disease is a devastating condition that usual y affects patients with persistent symptomatology and long-termdisability. Prompt and aggressive institution of antibiotic therapy may be essential to prevent refractory disease. Increasing evidenceshows that antibiotics have a beneficial effect on the course of refractory Lyme disease even in cases where the patient is intolerant ofantibiotics or when a previous regimen has failed. Several months of therapy are often required to produce clear evidence ofimprovement. During this time, symptomatic treatment may be combined with antibiotic treatment.
When patients fail to respond or their conditions deteriorate after initiation of empiric therapy, a number of possibilities should beconsidered other than Jarisch-Herxheimer reaction. These include adverse events that limit treatment, al ergic history to medication,inappropriate or inadequate dosing regimen, compliance problems, incorrect medication, immune sequelae, and sequestering of theorganism (e.g., in the central nervous system). An alternative diagnosis or coinfection should also be considered.
Although there may be a potential role for symptomatic treatment in chronic Lyme disease, this approach has little support due to thestrong possibility of persistent infection. Owing to the potential hazard of immunosuppression and the poor outcome in one study,steroid therapy is not recommended. Surgical synovectomy is associated with significant morbidity and does not address neurologicpresentations; it should be reserved for knee pain failing antibiotic treatment. Intra-articular steroid injection may be useful as atemporizing procedure in patients with persistent knee pain but this runs the risk of masking persistent infection.
Symptomatic therapy (particularly anti-inflammatory medications, tricyclic antidepressants, selective serotonin re-uptake inhibitors,and hydroxychloroquine) may be useful in concert with antibiotics and in individuals failing antibiotics.
Hyperbaric oxygen therapy (HBOT) is under study but is not recommended for routine therapeutic use. Other treatments, includingcholestyramine (CSM), antifungal therapy, and antiviral agents require further study.
Since patients are becoming more interested in alternative therapies (e.g., traditional Chinese medicine, anti-oxidants, hyperthermia,bee venom, naturopathy and homeopathy), physicians should be prepared to address questions regarding these topics.
The outcome of treating fibromyalgia secondary to Lyme disease with nonantibiotic regimens has been poor. The most encouragingclinical trial showed success in only one of 15 patients and only modest improvement in 6 of 15 individuals with fibromyalgia despite 2years of treatment.
Antibiotic therapy has been much more effective than supportive therapy in symptomatic patients with fibromyalgia secondary to Lymedisease.
Fibromyalgia treatment alone without antibiotics raises the risk of conversion to refractory chronic Lyme disease and/or exacerbationof an undiagnosed persistent infection and is not recommended. Increasingly, clinicians do not feel comfortable treating fibromyalgiain Lyme disease without antibiotics.
Several studies of patients with Lyme disease have recommended that antibiotics be discontinued after 30 days of treatment. Complicating the decision to stop antibiotics is the fact that some patients present with disease recurrence after the resolution of theirinitial Lyme disease symptoms. This is consistent with incomplete antibiotic therapy. Although the optimal time to discontinueantibiotics is unknown, it appears to be dependent on the extent of symptomatology, the patient’s previous response to antibiotics,and the overal response to therapy (see below).
Rather than an arbitrary 30-day treatment course, the patient’s clinical response should guide duration of therapy. Patients musttherefore be careful y evaluated for persistent infection before a decision is made to withhold therapy.
The decision to discontinue antibiotics should be made in consultation with the patient and should take into account such factors asthe frequency and duration of persistent infection, frequency of recurrence, probability of refractory Lyme disease, gains withantibiotics, the importance to the patient of discontinuing antibiotics, and potential for careful fol ow-up.
The ideal approach would be to continue therapy for Lyme disease until the Lyme spirochete is eradicated. Unfortunately there iscurrently no test available to determine this point. Therefore, the clinician must rely on the factors outlined above to decide on thelength of antibiotic therapy for chronic Lyme disease.
There is compel ing evidence that Lyme disease can result in serious and potential y refractory il ness. Use of alternative antibiotics totreat early Lyme disease with erythema migrans is general y not indicated unless coinfection is suspected.
The ILADS Working Group believes that the risk of alternative antibiotics is acceptable in selected Lyme disease patients presentingwith chronic Lyme disease. Alternative antibiotics include less commonly used oral antibiotics (cefixime, cefdinir, metronidazole) andintravenous antibiotics (imipenem, azithromycin). The role of alternative antibiotics in low-risk patients is less certain and there is lessconsensus among the guideline developers as to whether the potential benefits outweigh the risks.
Therapy for polymicrobial infection in Lyme disease is a rapidly changing area of clinical practice. Uncomplicated Lyme disease maybe managed without addressing coinfection by means of standard oral or parenteral antibiotic therapy. Some but not al expertsrecommend therapy for subclinical or chronic coinfection with Ehrlichia, Babesia, or Bartonella on the basis of their belief thatresponses are more prompt with this approach.
The dose, duration, and type of treatment for coinfections have not been defined. Published reports of coinfection are limited to asmal number of patients treated in open-label, nonrandomized studies. Doxycycline has been indicated for Ehrlichia. A recentlypublished randomized trial determined that treatment of severe Babesia microti with the combination of atovaquone and azithromycinwas as effective as the use of standard oral therapy with clindamycin and quinine.
The decision to use alternative antibiotics should be based on the individual case, including a careful assessment of the patient’s riskfactors and personal preferences. Patients managed in this way must be careful y selected and considered reliable for fol ow-up. Further control ed studies are needed to address the optimal antimicrobial agents for coinfections and the optimal duration of therapy. CLINICAL ALGORITHM(S) EVIDENCE SUPPORTING THE RECOMMENDATIONS TYPE OF EVIDENCE SUPPORTING THE RECOMMENDATIONS
The type of supporting evidence is not specifical y stated for each recommendation. IDENTIFYING INFORMATION AND AVAILABILITY BIBLIOGRAPHIC SOURCE(S)
Evidence-based guidelines for the management of Lyme disease. Expert Rev Anti Infect Ther 2004;2(1 Suppl):S1-13. [66references]
Not applicable: The guideline was not adapted from another source. DATE RELEASED GUIDELINE DEVELOPER(S)
International Lyme and Associated Diseases Society - Disease Specific Society
SOURCE(S) OF FUNDING
International Lyme and Associated Diseases Society
GUIDELINE COMMITTEE COMPOSITION OF GROUP THAT AUTHORED THE GUIDELINE Working Group Members: Daniel Cameron, MD, MPH, Internal Medicine and Epidemiology, Mt. Kisco, New York; Andrea Gaito, MD,Rheumatology, Basking Ridge, New Jersey; Nick Harris, PhD, Immunology, Pal Alto, California; Gregory Bach, DO, Family andIntegrative Medicine, Colmar, Pennsylvania; Sabra Bel ovin, MD, Family Practice, Portsmouth, Virginia; Kenneth Bock, MD, FamilyPractice, Rhineback, New York; Steven Bock, MD, Family Practice, Rhineback, New York; Joseph Burrascano, MD, Internal Medicine,East Hampton, New York; Constance Dickey, RN, Registered Nurse, Hampden, Maine; Richard Horowitz, MD, Internal Medicine,Hyde Park, New York; Steven Phil ips, MD, Internal Medicine, Ridgefield, Connecticut; Laurence Meer-Scherrer, MD, InternalMedicine, Flamatt, Switzerland; Bernard Raxlen, MD; Psychiatry, Greenwich, Connecticut; Virginia Sherr, MD, Psychiatry, Hol and,Pennsylvania; Harold Smith, MD, Emergency Medicine, Danvil e, Pennsylvania; Pat Smith, President, Lyme Disease Association, Inc.,Jackson, New Jersey; Raphael Stricker, MD, Hematology and Immunotherapy, San Francisco, California
FINANCIAL DISCLOSURES/CONFLICTS OF INTEREST GUIDELINE STATUS
This is the current release of the guideline. GUIDELINE AVAILABILITY
Electronic copies: Not available at this time.
Print copies: Available from the International Lyme and Associated Diseases Society, PO Box 341461, Bethesda, Maryland 20827–1461; Phone: (301) 263-1080; Fax: (301) 263-0776; Email:
AVAILABILITY OF COMPANION DOCUMENTS PATIENT RESOURCES NGC STATUS
This NGC summary was completed by ECRI on August 26, 2004. The information was verified by the guideline developer on October13, 2004. This summary was updated by ECRI Institute on October 3, 2007 fol owing the U.S. Food and Drug Administration (FDA)advisory on Rocephin (ceftriaxone sodium). This summary was updated by ECRI Institute on November 6, 2007, fol owing the U.S. Food and Drug Administration advisory on Antidepressant drugs. COPYRIGHT STATEMENT
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