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Te efcacy of alternative nonpenicillin Penicillin Allergy zoloft 100mg. HIV-infected 25mg zoloft, penicillin-allergic patients regimens in HIV-infected persons has not been well studied 100 mg zoloft. Patients with penicillin allergy whose com- treated with penicillin (see Management of Patients Who pliance with therapy or follow-up cannot be ensured should Have a History of Penicillin Allergy) zoloft 50 mg. Tese therapies should be desensitized and treated with penicillin (see Management be used only in conjunction with close serologic and clinical of Patients Who Have a History of Penicillin Allergy) zoloft 50mg. Limited clinical studies zoloft 25 mg, along with biologic and use of alternatives to penicillin has not been well studied in pharmacologic evidence zoloft 100 mg, suggest that ceftriaxone might be HIV-infected patients zoloft 25mg. Tese therapies should be used only in efective (229 50 mg zoloft,230) 100mg zoloft. However, the optimal dose and duration conjunction with close serologic and clinical follow-up. Latent Syphilis Among HIV-Infected Persons neurosyphilis Among HIV-Infected Persons Treatment Treatment HIV-infected persons with latent syphilis should be treated HIV-infected patients with neurosyphilis should be treated according to the stage-specifc recommendations for HIV- according to the recommendations for HIV-negative patients negative persons. If CSF pleocytosis was present initially, a CSF examina- • Treatment of late latent syphilis or syphilis of unknown tion should be repeated every 6 months until the cell count duration among HIV-infected persons is benzathine is normal. Follow-up CSF examinations also can be used to penicillin G, at weekly doses of 2. If the cell count has not decreased after 6 All HIV-infected persons with syphilis and neurologic months or if the CSF is not normal after 2 years, retreatment symptoms should undergo immediate CSF examination. CD4 count of ≤350 cells/ml and/or an RPR titer of ≥1:32 Special Considerations (204,225,226); however unless neurologic symptoms are pres- ent, CSF examination in this setting has not been associated Penicillin Allergy. HIV-infected, penicillin-allergic with improved clinical outcomes. Several small observational studies Patients should be evaluated clinically and serologically conducted in HIV-infected patients with neurosyphilis sug- at 6, 12, 18, and 24 months after therapy. If, at any time, gest that ceftriaxone 1–2 g IV daily for 10-14 days might be clinical symptoms develop or nontreponemal titers rise efective as an alternate agent (218,229,230). Most states mandate screening at the frst specialists. Evidence is insufcient to recommend specifc prenatal visit for all women (231); antepartum screening by regimens for these situations. Pregnant nancy are at risk for premature labor and/or fetal distress if the women with reactive treponemal screening tests should have treatment precipitates the Jarisch-Herxheimer reaction (236). In Tese women should be advised to seek obstetric attention after populations in which use of prenatal care is not optimal, RPR treatment if they notice any fever, contractions, or decrease in test screening and treatment (if the RPR test is reactive) should fetal movements. Stillbirth is a rare complication of treatment, be performed at the time that pregnancy is confrmed (232). All patients who have syphilis should be ofered syphilis is high and for patients at high risk, serologic testing testing for HIV infection. Inadequate maternal treatment is likely unless an adequate treatment history is documented clearly in if delivery occurs within 30 days of therapy, if clinical signs of the medical records and sequential serologic antibody titers infection are present at delivery, or if the maternal antibody have declined. Serofast low antibody titers might not require titer at delivery is fourfold higher than the pretreatment titer. Evidence is See General Principles, Management of Sex Partners. Special Considerations Recommended Regimen Penicillin Allergy Pregnant women should be treated with the penicillin regimen For treatment of syphilis during pregnancy, no proven appropriate for their stage of infection. Pregnant women who have a history of penicillin allergy should be desensitized and treated with penicillin. Oral step-wise penicillin dose challenge or skin other Management Considerations testing might be helpful in identifying women at risk for acute Some evidence suggests that additional therapy can be allergic reactions (see Management of Patients Who Have a beneficial for pregnant women in some settings (e. Erythromycin and azithromycin should not be have primary, secondary, or early latent syphilis) (235). When used, because neither reliably cures maternal infection or treats syphilis is diagnosed during the second half of pregnancy, an infected fetus (234). Data are insufcient to recommend management should include a sonographic fetal evaluation ceftriaxone for treatment of maternal infection and prevention for congenital syphilis, but this evaluation should not delay of congenital syphilis. Sonographic signs of fetal or placental syphilis (i. All HIV- All infants born to mothers who have reactive nontrepone- infected women should be evaluated for syphilis and receive mal and treponemal test results should be evaluated with a treatment as recommended. Data are insufcient to recom- quantitative nontreponemal serologic test (RPR or VDRL) mend a specifc regimen for HIV-infected pregnant women performed on infant serum, because umbilical cord blood can (see Syphilis Among HIV-Infected Patients). No commercially available immuno- Efective prevention and detection of congenital syphilis globulin (IgM) test can be recommended. Moreover, as part of the umbilical cord using specifc fuorescent antitreponemal anti- management of pregnant women who have syphilis, infor- body staining is suggested. Darkfeld microscopic examination mation concerning the treatment of sex partners should be of suspicious lesions or body fuids (e. Routine screening of newborn sera or umbilical cord blood Te following scenarios describe the evaluation and treat- is not recommended. Screening can be performed using congenital syphilis; either a nontreponemal or treponemal test. No infant or mother should Recommended Evaluation leave the hospital unless maternal serologic status has been documented at least once during pregnancy; in communities • CSF analysis for VDRL, cell count, and protein** and populations in which the risk for congenital syphilis is • Complete blood count (CBC) and diferential and plate- high, documentation should also occur at delivery. Terefore, treatment decisions frequently must congenital syphilis. Values as high as 25 white blood cells (WBCs)/mm3 and/or protein of 150 mg/dL might occur among normal neonates; some specialists, however, clinical, laboratory, or radiographic evidence of syphilis in the recommend that lower values (i. Other causes of elevated values should be considered when an infant is being evaluated for congenital syphilis. Data are insufcient regarding the use of other antimicrobial agents (e. When possible, If the mother has untreated early syphilis at delivery, 10 a full 10-day course of penicillin is preferred, even if ampicil- days of parenteral therapy can be considered. Te use of agents Scenario 3 other than penicillin requires close serologic follow-up to assess adequacy of therapy. In all other situations, the maternal history Infants who have a normal physical examination and a of infection with T. For instance, a lumbar puncture might document serum quantitative nontreponemal serologic titer the same or CSF abnormalities that would prompt close follow-up. Other less than fourfold the maternal titer and the tests (e. Passively transferred maternal Older infants and children aged ≥1 month who are identi- treponemal antibodies can be present in an infant until age fed as having reactive serologic tests for syphilis should have 15 months; therefore, a reactive treponemal test after age 18 maternal serology and records reviewed to assess whether months is diagnostic of congenital syphilis. If the nontrepone- they have congenital or acquired syphilis (see Primary and mal test is nonreactive at this time, no further evaluation or Secondary Syphilis and Latent Syphilis, Sexual Assault or Abuse treatment is necessary. If the nontreponemal test is reactive at of Children). Any child at risk for congenital syphilis should age 18 months, the infant should be fully (re)evaluated and receive a full evaluation and testing for HIV infection. Recommended Evaluation Infants whose initial CSF evaluations are abnormal should • CSF analysis for VDRL, cell count, and protein undergo a repeat lumbar puncture approximately every 6 • CBC, diferential, and platelet count months until the results are normal. A reactive CSF VDRL • Other tests as clinically indicated (e. Aqueous crystalline penicillin G 200,000–300,000 units/kg/day IV, administered as 50,000 units/kg every 4–6 hours for 10 days Special Considerations Penicillin Allergy If the child has no clinical manifestations of disease, the Infants and children who require treatment for syphilis CSF examination is normal, and the CSF VDRL test result is but who have a history of penicillin allergy or develop an negative, treatment with up to 3 weekly doses of benzathine allergic reaction presumed secondary to penicillin should be penicillin G, 50,000 U/kg IM can be considered. Tis treatment also would Penicillin Shortage be adequate for children who might have other treponemal infections. During periods when the availability of penicillin is com- promised, the following is recommended (see http://www. All seroreactive infants (or infants whose mothers were 1. For infants with clinical evidence of congenital syphilis seroreactive at delivery) should receive careful follow-up (Scenario 1), check local sources for aqueous crystalline examinations and serologic testing (i. If IV penicillin G is every 2–3 months until the test becomes nonreactive or the limited, substitute some or all daily doses with procaine titer has decreased fourfold. Nontreponemal antibody titers penicillin G (50,000 U/kg/dose IM a day in a single daily should decline by age 3 months and should be nonreactive dose for 10 days). Te serologic with careful clinical and serologic follow-up. Ceftriaxone must response after therapy might be slower for infants treated after be used with caution in infants with jaundice. If these titers are stable or increase after ≥30 days, use 75 mg/kg IV/IM a day in a single daily dose age 6–12 months, the child should be evaluated (e. For older infants, the dose should be enteral penicillin G. Terefore, ceftriaxone should be used in consultation who have had a severe reaction to penicillin stop expressing pen- with a specialist in the treatment of infants with congenital icillin-specifc IgE (238,239). Management may include a repeat CSF examination safely with penicillin. Penicillin skin testing with the major and at age 6 months if the initial examination was abnormal. For infants without any clinical evidence of infection at high risk for penicillin reactions (238,239). Although these (Scenario 2 and Scenario 3), use reagents are easily generated and have been available for more a. Manufacturers are working to ensure ceftriaxone is inadequate therapy. For premature infants who have no other clinical evidence accompanying minor determinant mixture. Skin-test–positive patients should be desensitized Evidence is insufcient to determine whether infants who before initiating treatment. Patients who have positive test results should be desensitized. One approach suggests that persons Management of Persons Who with a history of allergy who have negative test results should be regarded as possibly allergic and desensitized. Another Have a History of Penicillin Allergy approach in those with negative skin-test results involves test- No proven alternatives to penicillin are available for treating dosing gradually with oral penicillin in a monitored setting in neurosyphilis, congenital syphilis, or syphilis in pregnant women. Penicillin also is recommended for use, whenever possible, in If the major determinant (Pre-Pen) is not available for skin HIV-infected patients. In patients with reactions not likely to be IgE-mediated, or hypotension). Readministration of penicillin to these patients outpatient-monitored test doses can be considered. Because anaphylactic reactions to penicillin can be fatal, every efort should be made Penicillin Allergy Skin Testing to avoid administering penicillin to penicillin-allergic patients, unless they undergo acute desensitization to eliminate anaphy- Patients at high risk for anaphylaxis, including those who lactic sensitivity. Skin-test reagents for identifying persons at risk for adverse reactions to penicillin* skin-test reagents before being tested with full-strength reagents. In these situations, patients should be tested in a Major Determinant monitored setting in which treatment for an anaphylactic • Benzylpenicilloyl poly-L-lysine (PrePen) (AllerQuest, reaction is available. If possible, the patient should not have Plainville Connecticut) (6 x 10-5M). Te underlying epidermis is pierced with * Adapted from Saxon A, Beall GN, Rohr AS, Adelman DC. Immediate hypersensitivity reactions to beta-lactam antibiotics. Ann Intern Med a 26-gauge needle without drawing blood. Beall and test is positive if the average wheal diameter after 15 minutes Annals of Internal Medicine. Te histamine controls should be positive to frozen source. Intradermal Test Diseases Characterized by If epicutaneous tests are negative, duplicate 0. Te margins of the Urethritis, as characterized by urethral infammation, can wheals induced by the injections should be marked with a ball result from infectious and noninfectious conditions. An intradermal test is positive if the average wheal if present, include discharge of mucopurulent or purulent diameter 15 minutes after injection is >2 mm larger than the material, dysuria, or urethral pruritis. Asymptomatic infections initial wheal size and also is >2 mm larger than the negative are common. Tis is a straight- Gram-stain microscopy, frst void urine with microscopy, and forward, relatively safe procedure that can be performed orally leukocyte esterase) are not available, patients should be treated or IV. Although the two approaches have not been compared, with drug regimens efective against both gonorrhea and oral desensitization is regarded as safer and easier to perform. Further testing to determine the specifc etiology Patients should be desensitized in a hospital setting because seri- is recommended because both chlamydia and gonorrhea are ous IgE-mediated allergic reactions can occur. Desensitization reportable to health departments and a specifc diagnosis might usually can be completed in approximately 4–12 hours, after improve partner notifcation and treatment. Culture, nucleic which time the frst dose of penicillin is administered. After acid hybridization tests, and NAATs are available for the detec- desensitization, patients must be maintained on penicillin tion of both N. Culture and continuously for the duration of the course of therapy.

Dose-related sedation may occur with dopamine ago- positron emission tomography (PET) (95) and clinical ben- nists (69 zoloft 100mg,78) zoloft 50 mg, as with other dopaminergic agents including efits particularly for patients experiencing mild to moderate levodopa zoloft 100 mg. More recently 25mg zoloft, sudden episodes of unintended motor fluctuations 25 mg zoloft. Double-blind placebo-controlled clini- sleep while at the wheel of a motor vehicle have been de- cal trials in fluctuating PD patients demonstrate that scribed in PD patients and attributed to dopamine agonists COMT inhibitors increase the duration of beneficial effect (85) zoloft 50mg. The episodes were termed 'sleep attacks' because they following a single levodopa dose (96) zoloft 25mg. They also provide an occurred suddenly zoloft 25 mg, although others have argued that there increase daily 'on' time of 15% to 25% 50mg zoloft, a decrease in is no evidence to support the concept of a sleep attack even 'off' time of 25% to 40% 100 mg zoloft, improvement in UPDRS motor in narcolepsy. They have suggested that it is more likely scores, and a reduction in levodopa dose requirement of that these patients have unintended sleep episodes as a mani- 15% to 30% (97–100). Benefits with COMT inhibitors festation of excess daytime sedation due to nocturnal sleep have also been observed in nonfluctuating PD patients with disturbances that occur in 80% to 90% of PD patients and a stable response to levodopa. Two placebo-controlled trials to the sedative effect of dopaminergic medications (86). It showed improved motor scores and reduced levodopa dose is now apparent that these types of episodes can be associ- requirements in the group receiving the COMT inhibitor ated with all dopaminergic agents including levodopa (87). Physicians should be aware of the potential of dopaminergic There has also been interest in using COMT inhibitors agents to induce sleepiness, and that patients themselves from the time levodopa is first initiated in order to reduce may not be aware that they are sleepy. To detect excess the risk of developing motor complications (103). As de- sleepiness and to thereby introduce appropriate manage- scribed in the section on motor complications, laboratory ment strategies, it is necessary to employ sleep question- evidence supports the notion that treatment for PD patients naires such as the Epworth sleepiness scale, which inquires should be employed in such a way as to try and avoid pulsa- into the propensity to fall asleep and does not rely upon tile stimulation of dopamine receptors (51). Indeed, there subjective estimates of sleepiness (88). However, these patients Catechol O-Methyltransferase (COMT) eventually require levodopa, and when levodopa is adminis- Inhibitors tered the frequency of motor complications increases. It Orally ingested levodopa is massively transformed in the therefore has been postulated that administering levodopa periphery by two enzymatic systems—AADC and from the time it is first introduced with a COMT inhibitor 1802 Neuropsychopharmacology: The Fifth Generation of Progress to extend its half-life and deliver levodopa to the brain in data indicate that tolcapone is the more potent agent. How- a more continuous fashion might further reduce the risk of ever, because of the greater risk of hepatotoxicity and diar- motor complications. Based on a similar hypothesis, studies rhea, entacapone has become the more widely employed comparing controlled-release levodopa to regular levodopa COMT inhibitor. It should be emphasized that COMT failed to demonstrate any difference between the two formu- inhibitors provide antiparkinsonian benefit only when used lations (104,105). However, controlled-release formula- as an adjunct to levodopa. Further, the drug was prescribed advance in the medical treatment of PD and may be useful twice daily in these studies, and that may not have been in all stages of the illness (110). Used in combination with frequent enough to prevent fluctuations in plasma levodopa levodopa, they extend the half-life of levodopa, smooth the concentrations. Clinical trials to test this hypothesis using plasma levodopa concentration curve, and enhance clinical entacapone as an adjunct to levodopa are currently being dopaminergic benefits. Dyskinesia is the most common, but best left to the Parkinson specialist. There are preliminary nausea, vomiting, and psychiatric complications may occa- data suggesting that they enhance motor function in the sionally occur. Both the benefits and dopaminergic adverse milder patient with a stable response to levodopa, and this effects develop within hours to days after initiating treat- is being further evaluated. In general, they are easy to manage by simply reduc- to suggest that administering levodopa with a COMT in- ing the dose of levodopa (by approximately 15% to 30%), hibitor from the time it is first introduced may prevent not the dose of the COMT inhibitor. Dyskinesia is more pulsatile stimulation of dopamine receptors and minimize likely to be a problem in patients who already experience the risk of developing motor complications. The drugs are dyskinesia, and the need for a levodopa dose reduction can easy to use and require no titration. Dopaminergic side ef- be anticipated in these patients. An explosive diarrhea has fects tend to occur within days and can be managed by been seen in 5% to 10% of tolcapone-treated and necessi- tapering the levodopa dose. Because of the restrictions in tates discontinuing the drug. This has been much less of a the use of tolcapone due to liver toxicity, entacapone is now problem with entacapone and rarely requires stopping the the COMT inhibitor of choice. Brownish-orange urine discoloration may occur with tablet will soon be developed that contains the combination either drug due to accumulation of a metabolite. This is a of levodopa, an AADC inhibitor, and a COMT inhibitor. Of greater seriousness is the problem of liver toxicity that Other Antiparkinson Agents has been reported in association with tolcapone (106). No Anticholinergics evidence of liver dysfunction was detected in preclinical tox- icity studies, but in clinical trials elevated liver transaminase Anticholinergic drugs were first used as a treatment for PD levels were observed in 1% to 3% of patients. For this rea- in the 1860s, using extracts from the alkaloids Atropa bella- son, liver monitoring was required. Following approval of donna and Hyscyamus niger, which contain hyosciamine and the drug, there have been reports of four cases of severe scopolamine (111,112). Synthetic anticholinergic drugs liver dysfunction leading to the death of three of the individ- were developed in the 1940s, and they became the mainstay uals (106,107). These observations led to the drug being of PD treatment until the emergence of levodopa (113, withdrawn from the market in Europe and Canada and to 114). These drugs have largely been replaced by the newer the issuance of a 'black box' warning in the United States antiparkinsonian drugs, but are still used occasionally in the (108). This requires biweekly monitoring of liver enzymes modern era particularly for the treatment of tremor (115). No preclinical toxicity, neton), orphenadrine (Disipal), and procyclidine (Kema- clinical trial, or postmarket reports of liver dysfunction have drin). An interaction between dopaminergic and cholinergic been described to date with entacapone, and no laboratory neurons in the basal ganglia has long been recognized, and monitoring is required with its use (109). Cholinergic agents have been administered at a dose of 100 or 200 mg three times daily. Certainly when these agents neurons is regulated by cholinergic interneurons (119). De- are employed, side effects should be sought and the drug spite these observations, the relationship between the cho- discontinued when they occur. Clinical studies demonstrate that anticholinergic agents The discovery of the antiparkinson properties of the anti- provide a 10% to 25% improvement in rest tremor, whereas viral agent amantadine (Symmetrel) was fortuitous (125). In The primary mechanism of action of amantadine in PD is practice, anticholinergic agents can be used in early PD not established with certainty. The drug has been described patients to treat tremor when it is the predominant com- to increase dopamine release, block dopamine reuptake, and plaint and to delay the introduction of levodopa, provided stimulate dopamine receptors. It has also been shown to that cognitive function is preserved and that the patient have anticholinergic effects and weak NMDA receptor an- does not have narrow angle glaucoma or orthostatic hypo- tagonist properties (126–128). Improvement in akinesia, tension (see General Adverse Effects of DBS, below). Tri- rigidity, and tremor, as well as reduction in choice reaction hexyphenidyl is the most widely used anticholinergic agent time, have been described in uncontrolled studies, particu- in PD, although head-to-head comparisons have not been larly in mildly affected PD patients (125,129–131). With the recognition that amantadine provides NMDA Side effects are a major limiting factor with respect to receptor antagonism (128), there has been interest in the the use of anticholinergic drugs in PD. The most important notion that it might have antidyskinetic and even neuropro- of these are central, and consist of memory impairment, tective effects. The potential of the drug to interfere with confusion, hallucinations, sedation, and dysphoria (115). Studies in monkeys show that NMDA receptor ripheral side effects include dry mouth, dysuria, constipa- antagonists can improve dyskinesia (50). Preliminary clini- tion, dizziness due to orthostatic hypotension, tachycardia, cal trials suggest that the same is true in some PD patients nausea, blurred vision, and decreased sweating. Anticholin- (37,134), and this has now been confirmed in a double- ergic agents should be avoided in patients with narrow angle blind controlled study (135). The potential of amantadine glaucoma, and caution is required in using them in patients to provide neuroprotective effects is based on evidence sug- with prostatic hypertrophy because of the risk of inducing gesting that excitotoxicity contributes to neuronal degenera- acute urinary retention. Anticholinergic drugs can enhance tion in PD (136,137). Indeed, one retrospective study did levodopa-induced choreiform dyskinesias, and orobuccal suggest that there was an increase in the survival of PD dyskinesias have been reported with anticholinergic therapy patients that had been treated with amantadine (138). If the decision is made to discontinue anticho- The elimination half-life of amantadine is 10 to 30 hours, linergics, this should always be done gradually to avoid with- and the medication is typically administered in dosages of drawal effects and acute exacerbation of parkinsonism 100 mg two to three times per day. Anticholinergic agents that are relatively selective for and nightmares that limit its usefulness. Amantadine has bladder cholinergic receptors such as tolterodine tartrate also been associated with livedo reticularis, ankle edema, and (Detrol), and oxybutynin (Ditropan) can be used to treat peripheral neuropathy. If amantadine must be withdrawn, it bladder instability (123). Anticholinergic agents that are rel- should be done gradually as some patients may experience atively selective for salivary gland receptors such as glycopyr- dramatic worsening of PD on withdrawal. In conclusion, amantadine can be used in the initial Because of their adversity profile, and particularly their stages of PD to provide some symptomatic benefit and to tendency to induce cognitive impairment, anticholinergic delay the need for levodopa. It can also be used as an adjunct agents are not commonly used in the treatment of PD. They to levodopa to try to control levodopa-induced dyskinesia. However, there is evidence sug- mental status must be closely monitored particularly in pa- gesting that levodopa and other dopaminergic agents pro- tients with advanced disease or preexisting cognitive impair- 1804 Neuropsychopharmacology: The Fifth Generation of Progress ment. As it is difficult to withdraw in many instances, many mortality in patients receiving the combination of levodopa- physicians do not use this drug as a first-line therapy. However, the statistical methods used in this study were questioned (158), and in- Selegiline creased mortality has not been confirmed in a metaanalysis Selegiline (Deprenyl, Eldepryl) is a relatively selective inhib- evaluating mortality in all other prospective trials of selegi- itor of monoamine oxidase-B (MAO-B). However, it is primarily used in the treatment Clinical trials are consistent with this notion, but might be of early PD patients as a putative neuroprotective agent. The drug is This was based on two important observations that sug- generally well tolerated, and claims of increased mortality gested that an MAO-B inhibitor might alter the natural have not been substantiated. First, the neurotoxin MPTP causes parkin- ment and personal philosophy as to whether or not to use sonism (140) by way of an MAO-B–catalyzed oxidation selegiline as a putative neuroprotective drug. In the labora- DISEASE tory, selegiline has been shown to protect nigral dopami- nergic neurons in cell cultures and in MPTP-treated animals In the past few years, the renaissance of functional neurosur- (142,143). Prospective double-blind clinical trials in previ- gery has transformed our vision of PD therapy. Functional ously untreated PD patients have demonstrated that selegi- neurosurgery for movement disorders dates back to the be- line delays the emergence of clinical dysfunction as deter- ginning of the 20th century, with the introduction of pyra- mined by the need for levodopa and the progression of midal tract lesions or dorsal root sections (160–162). However, were unfortunately characterized by their unacceptable mor- post hoc analyses have demonstrated that selegiline has bidity. Lesions of the basal ganglia as a treatment for PD symptomatic effects that might account for these benefits. These confound interpretation of these studies (146). In These procedures provided some benefits for tremor and addition, the disease continues to progress, and initial bene- rigidity, but adverse events were common and there was an fits do not appear to persist (147,148). Surgery therapies for PD became more widely possible beneficial effects of selegiline, it is now clear that accepted with the introduction of stereotactic techniques the drug has clear neuroprotective effects for dopaminergic (169) and the determination that lesions of the thalamus neurons in both in vitro and in vivo laboratory models (see could provide benefits with fewer adverse events (170). Further, it is now clear that neuropro- With the introduction of levodopa, surgery for PD was al- tection with selegiline does not depend on MAO-B inhibi- most abandoned. How- (GAPDH) and preventing its translocation to the nucleus. These find- may thus have overstated the benefits that can be achieved ings, indicating that selegiline is an antiapoptotic drug, are (173). There is little doubt that surgical techniques offer the particularly relevant to PD, where there is evidence that cell potential to provide benefit to PD patients with advanced death occurs by way of an apoptotic process (155). In levodopa-treated patients it are required in order to determine their true value (174). Its amphetamine Ablative Procedures metabolite can also cause insomnia, and for this reason the Thalamotomy second dose is usually not administered after 12 noon. Using the posterolateral pallidum as a target, consistently indicate that the ventral anterior and ventral several surgical groups have now reported benefits in PD lateral thalamic nuclei, the STN and the GPi, are overactive patients (195–197). The most dramatic finding is a consis- in PD (175,176), probably reflecting increased inhibitory tent long-lasting abolition of contralateral dyskinesia; anti- output from the GPi. Cooper (170) and Hassler and Riech- parkinsonian benefits are more modest (198,199). Compli- ert (177) noted in the 1950s that thalamic lesions could cations occur in 3% to 10% of patients and are primarily relieve contralateral tremor. Their experience led to thala- visual in nature, although cognitive impairment, sensory motomy becoming the preferred surgical procedure for the deficits, and motor weakness may all occur. Bilateral pallido- treatment of tremor-predominant forms of PD. Their tomy is associated with increased risk of disabling dysphagia, choice of target was facilitated and supported by electro- dysarthria, and cognitive impairment (200,201), and has physiologic studies demonstrating abnormal tremor syn- largely been abandoned with the availability of stimulation chronous electrical activity in this region (178–180). Current pathophysiologic models of PD explain and Narabayashi (181,182) subsequently used these tech- the improvement in parkinsonism, but do not explain the niques to conclude that lesions in the VIM nucleus of the striking antidyskinetic effect of pallidotomy (202). It has thalamus were most effective in reducing contralateral been proposed that the antidyskinetic effect of pallidotomy tremor. Studies reported a consistent reduction in contralat- may be due to elimination of an abnormal firing pattern in eral tremor, but it is less certain that there are benefits with pallidal output neurons that are providing misinformation regard to rigidity, and there is virtually no benefit for more to cortical motor regions that result in the emergence of disabling features such as bradykinesia or postural impair- dyskinesia (42). These studies also suggested that thala- In summary, unilateral pallidotomy provides consistent motomy has the potential to reduce or prevent the develop- and dramatic improvement in contralateral levodopa-in- ment of levodopa-induced dyskinesia (183,184,187–189). However, improvement in parkinsonian In recent studies, persistent morbidity associated with uni- features is modest and the procedure is associated with le- lateral thalamotomy occurs in less than 10% of patients.

zoloft 100mg

zoloft 100 mg

The rate of Conditioned Place Preference acquisition of self-administration and/or the number of ani- The conditioning procedure used to study sensitization is mals acquiring stable drug self-administration then is deter- identical to that described above except that the dose of mined zoloft 25mg. Because sensitization is defined as an increase in the conditioning drug or the number of environmental pairings potency and/or efficacy of a drug in producing a particular used typically are those that are ineffective in producing response following its repeated administration zoloft 100 mg, the rate of a conditioned response in previously drug-naive animals zoloft 25 mg. Several laboratories have shown a drug zoloft 100mg, and place conditioning can be initiated at various that the rate of acquisition of psychostimulant self-adminis- time points following the cessation of drug administration zoloft 50 mg. Alternatively 50 mg zoloft, by employing of sensitization (38 25 mg zoloft,71) 100mg zoloft. The prior administration of am- doses that are subthreshold and threshold for producing a phetamine also increases the acquisition rate of cocaine self- conditioned response zoloft 50mg, changes in drug potency and efficacy administration (and 25mg zoloft, conversely, the prior administration of following prior drug exposure can be determined. Using cocaine increases the acquisition rate of amphetamine self- these procedures, long-lasting sensitization and cross-sensi- administration), suggesting that cross-sensitization develops tization to the conditioned reinforcing effects of opiates and to the positive reinforcing effects of psychostimulants. Sensitization to the conditioned reinforcing effects of cocaine. Rats received once daily home cage injections of cocaine or saline for 5 days. Place conditioning (two cocaine; two saline) commenced 3 days later. Cocaine was ineffective in producing a conditioned response after two environmental pairings. In animals with a prior history of cocaine, doses of cocaine as low as5. Ordinate:Conditioning score defined as time in drug-paired environment minus time in saline-paired environment. Asterisks (*) denote significant place conditioning. Taken with permission from Shippenberg TS, Heidbreder C. Sensitization to the conditioned rewarding effects of cocaine: pharmacologic and temporal characteristics. Escalation in Drug Self-Administration reinstated rapidly at a level higher than that seen before Produced by aHistory of Drug Intake abstinence. Similar results have been observed in rats trained to self- A critical issue for the study of the neurobiology of addiction administer heroin intravenously. Two groups of rats were is to develop animal models for the transition between con- trained on 1-hour continuous access to intravenous heroin trolled/moderate drug intake and uncontrolled/excessive self-administration and then one group was allowed access drug intake. Animal models of increased drug intake based for 11 hours continuously. In the animals with 11-hour on prolonged exposure to drug now have been described in access, intake gradually increased over time, whereas in the rats for cocaine, heroin, and alcohol (1–3,76). The animals with 11-hour access to fers depending on the duration of access. With 1 hour of heroin were slower to extinguish heroin-seeking behavior. In contrast, with 6 hours produce dependence show a similar increase in baseline alco- of access per session, cocaine intake gradually escalated to hol intake long after acute withdrawal (76). Operant oral levels significantly above the training baseline (Fig. Abstinence of a month returned the esca- cient period to produce physical dependence on alcohol, lated intake to pre-escalation baseline, but escalation was detoxified, and then allowed a 2-week period of protracted 1390 Neuropsychopharmacology: The Fifth Generation of Progress FIGURE 97. A: In Long-Access (LgA) rats (n 12) but not in Short-Access (ShA) rats (n 12), mean total cocaine intake ( SEM) started to increase significantly fromsession 5 (p. B: During the first hour, LgA rats self-administered more infusions than ShA rats during sessions 5 to 8, 11, 12, 14, 15, and 17 to 22 (p. LgA rats took significantly more infusions than ShA rats at doses of 31. D: After escalation, LgA rats took more cocaine than ShA rats regardless of the dose (p. Transition from moderate to exces- sive drug intake: change in hedonic set point. Operant responding was enhanced during pro- contribute to drug craving and relapse to addiction. Indeed, tracted abstinence by 30% to 100% and remained elevated human studies have shown that the presentation of stimuli for 4 to 8weeks post acute withdrawal. ANIMAL MODELS OF RELAPSE: CONDITIONED REINFORCING EFFECTS OF Positive Reinforcing Effects of Stimuli DRUGS Associated with Drug Self- Administration: Conditioned The role of environmental stimuli in the control of drug- Reinforcement Paradigm taking behavior is a major focus of addiction research. This interest stems from the view that any account of drug abuse The conditioned reinforcement paradigm allows characteri- must address those factors that precede and motivate drug zation of the incentive value imparted on formerly neutral taking, as well as those that underlie the reinforcing conse- environmental stimuli that have been repeatedly associated quences of drug delivery. Environmental cues repeatedly with drug self-administration. In this paradigm, subjects paired with primary reinforcers can acquire incentive prop- usually are trained in an operant chamber containing two erties via classical conditioning processes (57,87,97). Responses on one lever result in the presentation of been postulated that these conditioned reinforcing effects a brief stimulus followed by a drug injection (active lever) Chapter 97: Recent Advances in Animal Models of Drug Addiction 1391 whereas responses on the other lever have no consequences ence of the conditioned stimulus than in its absence (73). The ability of the previous neutral, Similar results have been obtained in an operant runway drug-paired stimulus to maintain responding in the absence task (57). It is also apparent that environmental stimuli of drug injections provides a measure of the reinforcing predictive of cocaine self-administration reliably elicit drug- value of these stimuli. This procedure provides a stringent seeking behavior in experimental animals and that respond- test for the conditioned incentive effects of drugs because ing for these stimuli is highly resistant to extinction (39, responding for drug-associated stimuli occurs under extinc- 87,97). It also provides an animal model of drug craving because the incentive moti- Reinstatement of Extinguished Drug- vational effects of a stimulus are examined in the absence Seeking Behavior in an Animal Model of of drug taking. Relapse: Use of Discriminative Stimuli Rat models of 'relapse' induced by drug-related stimuli Second-Order Schedules also can involve the use of a drug-predictive discriminative Second-order schedules also can be used to evaluate the stimulus (S? This stimulus is paired with response-contin- conditioned reinforcing effects of drugs. To assess the effects gent presentation of a stimulus that has been contiguously of conditioned reinforcement, the number of responses with paired with drug presentations (i. For example, substitu- lever after prior extinction of alcohol-seeking behavior. Dis- tion of drug-paired stimuli with nondrug-paired stimuli ac- criminative stimuli signal the availability of a reinforcer, tually can decrease response rates (43). This maintenance and thereby provide motivation to engage in behavior that of performance with drug-paired stimuli appears to be anal- brings the organism into contact with the reinforcer. A con- ogous to the maintenance and reinstatement of drug seeking dition often associated with drug craving in humans is cog- in humans with the presentation of drug-paired stimuli nitive awareness of drug availability (63). In rats, a decrease in responding and an increase in stimuli, therefore, may have a prominent role in craving the latency to initiate responding occurs in response to with- and the resumption of drug-seeking behavior in abstinent holding a stimulus paired with cocaine self-administration individuals. The schedule can be repeated several times during a as a conditioned reinforcer, may contribute to the mainte- test session, resulting in multiple infusions of drug. How- nance of subsequent drug-seeking behavior once initiated. Associated with Intravenous Drug To investigate the role of drug-associated stimuli in the Self-Administration motivational effects of a history of cocaine self-administra- Extinction procedures provide measures of the incentive or tion, rats were trained to associate discriminative stimuli motivational effects of drugs by assessing the persistence of (S ) with response-contingent availability of intravenous drug-seeking behavior in the absence of response–contin- cocaine versus saline (97) (Fig. In this paradigm, subjects first are subjected to repeated extinction sessions during which co- trained to self-administer a drug until stable self-administra- caine, saline, and the respective S were withheld until the tion patterns are exhibited. Extinction sessions are identical rats reached extinction. Subsequent re-exposure to the co- to training sessions except that no drug is delivered after caine S , but not the nonreward S , produced strong re- the completion of the response requirement. The behavioral sig- degree of resistance to extinction and include the duration nificance of the cocaine S was further confirmed by the of extinction responding and the total number of responses fact that the rats initially tested in the presence of the nonre- emitted during the entire extinction session. The probability ward S showed complete recovery of responding when of reinstating responding under extinction conditions with subsequently presented with the cocaine S , but rats that drug-paired stimuli or even stimuli previously paired with had shown robust reinstatement ceased responding when drug withdrawal can be examined. These results Both stimulant and opiate self-administration have been support the hypothesis that learned responses to drug- consistently reinstated following priming injections of drug related environmental stimuli can be important factors in (31,55). Responding during extinction is greater in the pres- the reinstatement of drug-seeking in animals and provide 1392 Neuropsychopharmacology: The Fifth Generation of Progress ity in human alcoholics, the motivating effects of alcohol- related stimuli are highly resistant to extinction in that they retain their efficacy in eliciting alcohol-seeking behavior over more than 1 month of repeated testing (96). Place Conditioning Place conditioning procedures can be modified to serve as a model of relapse. Place aversions to opiate withdrawal last for over 8weeks (94) and are resistant to extinction. At- tempts to modify such conditioned effects could hypotheti- cally contribute to knowledge of the factors that contribute to relapse or 'craving. Reliability and Predictability Each of the techniques described has reliability and predic- tive validity. Presentation of stimuli associated with drug injection induces drug craving in humans and maintains responding in the conditioned reinforcement, second-order schedule, and extinction paradigms. The presence or ab- sence of cues associated with drug administration alters the reinstatement of extinguished drug-seeking behavior in pre- FIGURE 97. Lever-press responses during self-administration dictable ways. Training phase: cocaine-reinforced re- sponses during the final 3 days of the self-administration phase in rats (n 15) trained to associate S? No differences were observed between responses during the first and second daily hour of cocaine availability, and responses for cocaine or saline Although it is very difficult to find an animal model of any between rats designated for testing under S versus S condi- psychiatric disorder that mimics the entire syndrome, one tions during the initial 3 days of the reinstatement phase. The data were, therefore, collapsed across groups and daily cocaine can reasonably validate animal models for different symp- sessions for the purpose of this illustration. Extinction phase: ex- toms of mental disorders (32). In the realm of addiction tinction responses at criterion. The extinction criterion ( 4 re- research, the observation that animals readily self-administer sponses per session over 3 consecutive days) was reached within 16. Although intra- the S versus S condition during the reinstatement phase). Rein- venous drug self-administration meets the criteria of reliabil- statement phase: responses under the S (n 7) and S (n 8) ity, predictability, and face validity, it does not represent reinstatement conditions. Exposure to the S elicited significant recovery of responding in the absence of further drug availability. Other Responding in the presence of the S remained at extinction lev- aspects of the addiction syndrome can indeed be modeled, els. Taken with permission from Weiss F, Maldonado-Vlaar CS, but again, it is incorrect to consider any one of these an Parsons LH, et al. Control of cocaine-seeking behavior by drug- associated stimuli in rats: effects on recovery of extinguished op- animal model of addiction. The DSM-IV criteria for sub- erant-responding and extracellular dopamine levels in amygdala stance dependence and animal models relevant to their and nucleus accumbens. Proc Natl Acad Sci USA 2000;97: study are summarized in Table 97. Tolerance (criterion 1) and withdrawal (criterion 2) no longer define addiction, as illustrated by the change in crite- ria outlined in DSM-III versus DSM-IIIR and DSM-IV (5–7); however, evidence is accumulating to suggest that a a powerful model for elucidating the neuropharmacologic common element associated with addiction is a motiva- basis for such effects that are related to the human concepts tional form of withdrawal that is reflected in a compromised of relapse and craving (97). This not only reaf- Cues associated with oral self-administration and avail- firms the importance of withdrawal in addiction (e. In addition, and the dimension of a persistent motivational change that may consistent with the well-established conditioned cue reactiv- be reflected in criteria 7 of the DSM-IV: 'continued use Chapter 97: Recent Advances in Animal Models of Drug Addiction 1393 TABLE 97. ANIMAL MODELS FOR THE CRITERIA OF DSM-IV DSM-IV Animal Models A. A maladaptive pattern of substance use, leading to clinically significant impairment or distress as occurring at any time in the same 12-month period: (1) Need for markedly increased amounts of substance to achieve (1) Tolerance to reinforcing effects: intoxication or desired effect; or markedly diminished effect with Cocaine continued use of the same amount of substance Opiates (2) The characteristic withdrawal syndrome for substance; or substance (2) Increased: (or closely related substance) is taken to relieve or avoid withdrawal Reward thresholds Anxiety-like responses symptoms Cocaine Cocaine Opiates Opiates Alcohol Alcohol Nicotine Tetrahydrocannabinol Tetrahydrocannabinol (3) Persistent desire or one or more unsuccessful efforts to cut down (3) Conditional positive reinforcing effects: or control substance use Cocaine Opiates Alcohol (4) Substance used in larger amounts or over a longer period than (4) Cocaine binge the person intended Opiate intake (dependent animals) Alcohol intake (dependent animals) Alcohol Deprivation Effect (5) Important social, occupational, or recreational activities given up (5) Choice paradigms or reduced because of substance use Behavioral economics—loss of elasticity (6) A great deal of time spent in activities necessary to obtain (6) Opiate self-administration during withdrawal substance, to use substance, or to recover from its effect Alcohol self-administration during withdrawal Progressive-ratio responding (7) Continued substance use despite knowledge of having a (7) Cocaine binge toxicity persistent problem that is likely to be caused or exacerbated by substance use From: American Psychiatric Association, 1994. Second-order schedules can be used as a measure of persistent desire to cut down or control substance use' and the conditioned reinforcing properties of drugs (43). Recent 'the substance taken in larger amounts than intended. The in general, drugs that are self-administered correspond to conditioned place preference paradigm also provides a mea- those that have high abuse potential in humans (60,61). Presumably, such states reflect some prolonged post acute The remaining criterion for substance dependence as de- withdrawal perturbation or vulnerability to reinstatement fined by DSM-IV can be linked to animal models by exten- of drug-seeking behavior and ultimately compulsive use. However, drug administration in the context of digms (20). Finally, 'continued substance use despite implementation of procedures designed to assess functional knowledge of having a persistent or recurrent physical or genomic activity (e. Drug addiction in humans has been characterized as oc- curring in several stages, although progress from one stage ACKNOWLEDGMENTS to the next is not inevitable. The first stage is initiation or acquisition, which may lead to habitual use, physical or The authors would like to thank Mike Arends for his help psychic dependence, and loss of control. An individual may with the preparation of this manuscript. This is publication stop taking a drug at any stage; however, relapse to drug number 13454-NP from The Scripps Research Institute. The extent Research was supported by National Institutes of Health to which the procedures discussed here model the human grants AA06420 and AA08459 from the National Institute condition to the point of reliability and predictive validity on Alcohol Abuse and Alcoholism, DK26741 from the Na- requires further assessment. Addiction is a chronic relapsing dis- search Program from the National Institute on Drug Abuse. As discussed, the motivating factors for the development, maintenance, and persistence of drug addic- REFERENCES tion can be broken down into four major sources of rein- 1. Transition from moderate to excessive forcement: positive reinforcement, negative reinforcement, drug intake: change in hedonic set point. Science 1998;282: conditioned positive reinforcement, and conditioned nega- 298–300.

This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed zoloft 25mg, the full report) may be included in professional journals 147 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising 50mg zoloft. Applications for commercial reproduction should be addressed to: NIHR Journals Library 100mg zoloft, National Institute for Health Research zoloft 50 mg, Evaluation 25 mg zoloft, Trials and Studies Coordinating Centre zoloft 100 mg, Alpha House 50 mg zoloft, University of Southampton Science Park zoloft 50mg, Southampton SO16 7NS zoloft 25 mg, UK zoloft 100mg. Stretching (including positional constraint-induced movement therapy) Eye-gaze skills stretching, splints) l Sensory/sensory integration l Adaptive/problem-solving skills Language development Endurance training (specific approaches mentioned: l Occupational performance coaching; Narrative/storytelling skills Cardiovascular fitness training Cognitive Orientation to daily Occupational Performance Reciprocal communication (e. Specific techniques: l Self-care/life skills baby-signing; intensive interaction) Constraint-induced movement Adjusting/changing a task to support a Aided Language Simulation therapy child to manage it independently Articulation therapy Bimanual training Providing equipment to enable child to engage in activities Breath support skills Proprioceptive neuromuscular facilitation l Seating Facial oral tract therapy l Postural management Hip and spine surveillance l Mobility (including powered) Dysphagia (swallowing, saliva control) l Small items (e. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals 149 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. APPENDIX 6 Physiotherapy Occupational therapy Speech and language therapy Hydrotherapy Changing the environment to support Augmentive and alternative engagement in activities or address communication systems Functional electrical stimulation care needs Feeding/drinking equipment Botulinum (botox) l Housing adaptations l Hoists Sports (e. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health Published by the NIHR Journals Library . He also reports a grant from the NIHR Public Health Research programme during the conduct of the study. Colin Green served as a member of the funding panel for the NIHR Programme Grants for Applied Research programme from 2009 to 2013. Colin Green (2007–13) and Siobhan Creanor (2013–present) served as members of the NIHR Research Funding Committee for the South West Region of the Research for Patient Benefit Programme. Intervention costs for this study were paid for by the Peninsula College of Medicine and Dentistry. Stuart Logan (NF-SI-0515–10062) and Rod Taylor (NF-SI-0514–10155) are NIHR senior investigators. This study was undertaken in collaboration with the Peninsula Clinical Trials Unit (CTU), a UK Clinical Research Collaboration-registered CTU in receipt of NIHR CTU support funding. None of the funders had any involvement in the Trial Steering Committee, data analysis, data interpretation, data collection or writing of the report. Cluster randomised controlled trial and economic and process evaluation to determine the effectiveness and cost-effectiveness of a novel intervention [Healthy Lifestyles Programme (HeLP)] to prevent obesity in school children. Public Health Research ISSN 2050-4381 (Print) ISSN 2050-439X (Online) This journal is a member of and subscribes to the principles of the Committee on Publication Ethics (COPE) (www. Print-on-demand copies can be purchased from the report pages of the NIHR Journals Library website: www. PHR programme The Public Health Research (PHR) programme, part of the National Institute for Health Research (NIHR), evaluates public health interventions, providing new knowledge on the benefits, costs, acceptability and wider impacts of non-NHS interventions intended to improve the health of the public and reduce inequalities in health. The scope of the programme is multi-disciplinary and broad, covering a range of interventions that improve public health. The Public Health Research programme also complements the NIHR Health Technology Assessment programme which has a growing portfolio evaluating NHS public health interventions. For more information about the PHR programme please visit the website: http://www. The final report began editorial review in November 2016 and was accepted for publication in February 2017. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. However, they do not accept liability for damages or losses arising from material published in this report. This report presents independent research funded by the National Institute for Health Research (NIHR). The views and opinions expressed by authors in this publication are those of the authors and do not necessarily reflect those of the NHS, the NIHR, NETSCC, the PHR programme or the Department of Health. If there are verbatim quotations included in this publication the views and opinions expressed by the interviewees are those of the interviewees and do not necessarily reflect those of the authors, those of the NHS, the NIHR, NETSCC, the PHR programme or the Department of Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. 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Public Health Research Editor-in-Chief Professor Martin White Director of Research and Programme Leader, UKCRC Centre for Diet and Activity Research (CEDAR), MRC Epidemiology Unit, Institute of Metabolic Science, School of Clinical Medicine, University of Cambridge; Visiting Professor, Newcastle University; and Director, NIHR Public Health Research Programme NIHR Journals Library Editor-in-Chief Professor Tom Walley Director, NIHR Evaluation, Trials and Studies and Director of the EME Programme, UK NIHR Journals Library Editors Professor Ken Stein Chair of HTA and EME Editorial Board and Professor of Public Health, University of Exeter Medical School, UK Professor Andrée Le May Chair of NIHR Journals Library Editorial Group (HS&DR, PGfAR, PHR journals) Dr Martin Ashton-Key Consultant in Public Health Medicine/Consultant Advisor, NETSCC, UK Professor Matthias Beck Professor of Management, Cork University Business School, Department of Management and Marketing, University College Cork, Ireland Dr Tessa Crilly Director, Crystal Blue Consulting Ltd, UK Dr Eugenia Cronin Senior Scientific Advisor, Wessex Institute, UK Dr Peter Davidson Director of the NIHR Dissemination Centre, University of Southampton, UK Ms Tara Lamont Scientific Advisor, NETSCC, UK Dr Catriona McDaid Senior Research Fellow, York Trials Unit, Department of Health Sciences, University of York, UK Professor William McGuire Professor of Child Health, Hull York Medical School, University of York, UK Professor Geoffrey Meads Professor of Wellbeing Research, University of Winchester, UK Professor John Norrie Chair in Medical Statistics, University of Edinburgh, UK Professor John Powell Consultant Clinical Adviser, National Institute for Health and Care Excellence (NICE), UK Professor James Raftery Professor of Health Technology Assessment, Wessex Institute, Faculty of Medicine, University of Southampton, UK Dr Rob Riemsma Reviews Manager, Kleijnen Systematic Reviews Ltd, UK Professor Helen Roberts Professor of Child Health Research, UCL Institute of Child Health, UK Professor Jonathan Ross Professor of Sexual Health and HIV, University Hospital Birmingham, UK Professor Helen Snooks Professor of Health Services Research, Institute of Life Science, College of Medicine, Swansea University, UK Professor Jim Thornton Professor of Obstetrics and Gynaecology, Faculty of Medicine and Health Sciences, University of Nottingham, UK Professor Martin Underwood Director, Warwick Clinical Trials Unit, Warwick Medical School, University of Warwick, UK Please visit the website for a list of members of the NIHR Journals Library Board: www. There is little evidence of effective obesity prevention programmes for children in this age group. Objective: To determine the effectiveness and cost-effectiveness of a school-based healthy lifestyles programme in preventing obesity in children aged 9–10 years. Design: A cluster randomised controlled trial with an economic and process evaluation. Setting: Thirty-two primary schools in south-west England. Intervention: The Healthy Lifestyles Programme (HeLP) ran during the spring and summer terms of Year 5 into the autumn term of Year 6 and included four phases: (1) building a receptive environment, (2) a drama-based healthy lifestyles week, (3) one-to-one goal setting and (4) reinforcement activities. Main outcome measures: The primary outcome measure was body mass index (BMI) standard deviation score (SDS) at 24 months post baseline measures (12 months post intervention). The secondary outcomes comprised waist circumference SDS, percentage body fat SDS, proportion of children overweight and obese at 18 and 24 months, accelerometer-assessed physical activity and food intake at 18 months, and cost-effectiveness. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals vii provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. ABSTRACT Results: We recruited 32 schools and 1324 children. We had a rate of 94% follow-up for the primary outcome. No difference in BMI SDS was found at 24 months [mean difference –0. No difference was found between the intervention and control groups in waist circumference SDS, percentage body fat SDS or physical activity levels. Self-reported dietary behaviours showed that, at 18 months, children in the intervention schools consumed fewer energy-dense snacks and had fewer negative food markers than children in the control schools. The cost of implementing the intervention was approximately £210 per child. The intervention was not cost-effective compared with control. The programme was delivered with high fidelity, and it engaged children, schools and families across the socioeconomic spectrum. Limitations: The rate of response to the parent questionnaire in the process evaluation was low. Although the schools in the HeLP study included a range of levels of socioeconomic deprivation, class sizes and rural and urban settings, the number of children for whom English was an additional language was considerably lower than the national average. Conclusions: HeLP is not effective or cost-effective in preventing overweight or obesity in children aged 9–10 years. Future work: Our very high levels of follow-up and fidelity of intervention delivery lead us to conclude that it is unlikely that school-based programmes targeting a single age group can ever be sufficiently intense to affect weight status. New approaches are needed that affect the school, the family and the wider environment to prevent childhood obesity. Trial registration: Current Controlled Trials ISRCTN15811706. Funding: This project was funded by the National Institute for Health Research (NIHR) Public Health Research programme and will be published in full in Public Health Research; Vol. See the NIHR Journals Library website for further project information. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals ix provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. CONTENTS Primary intention-to-treat analysis of body mass index standard deviation score at 24 months 28 Model diagnostics for the primary analysis of body mass index standard deviation score at 24 months 29 Secondary analysis of body mass index standard deviation score at 24 months 29 Subgroup analyses of body mass index standard deviation score at 24 months 30 Longitudinal analysis of body mass index standard deviation score 31 Primary analyses of secondary outcomes at 24 months (anthropometric measures only) 32 Primary analyses of outcomes at 18 months 32 Model diagnostics for the primary analysis of the secondary outcomes 37 Intraclass correlation coefficients 39 Complier average causal effect analysis 39 Chapter 4 Economic evaluation 41 Introduction 41 Methods 41 Estimating resource use and costs for delivery of the HeLP intervention 41 Development of modelling framework (Exeter Obesity Model) to estimate the cost-effectiveness of the HeLP intervention versus usual practice 44 Results 44 Estimating the resource use and cost of the HeLP intervention 44 A framework for the economic evaluation of HeLP 49 Discussion 68 Chapter 5 Process evaluation 71 Introduction 71 Aims 71 Research questions 71 Logic model 71 General methods 73 Section 1: process data collected from the intervention arm of the trial 73 Methods 73 Results 77 Summary 90 Section 2: mediation analyses 91 Background 91 Methods 91 Results 94 Summary 99 Conclusions from the process evaluation 100 Chapter 6 Discussion and conclusions 101 Summary of findings 101 Comparison with other studies 101 Understanding the lack of effectiveness 102 Trial strengths and limitations 103 Research recommendations 104 Conclusions 105 Acknowledgements 107 References 111 Appendix 1 Trial Steering Committee 121 x NIHR Journals Library www. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals xi provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals xiii provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. LIST OF TABLES TABLE 18 Unit costs (GBP) used to estimate cost of delivery of HeLP intervention 43 TABLE 19 Summary of school level characteristics for delivery of HeLP 45 TABLE 20 Resource use by staff type by type of contact (preparation, task and travel): total across 16 schools, 27 classes 46 TABLE 21 Resource use by school–class configuration: resource use by staff type and by type of contact (preparation, task and travel) 47 TABLE 22 Estimated cost (GBP) for delivery of HeLP (total cost across 16 schools, 27 classes) 48 TABLE 23 Estimated total cost (GBP) for delivery of HeLP by school-class configuration: one school and one, two and three classes 48 TABLE 24 Sensitivity analysis 1: estimated cost (GBP) for delivery of HeLP (total cost across 16 schools, 27 classes) using a higher unit cost (£25. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals xv provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals xvii provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals xix provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals xxi provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. Working with teachers, families and children, we C developed the Healthy Lifestyles Programme (HeLP), which aims to engage and support children and families to make healthy food and activity choices. We designed a study to understand whether or not HeLP can prevent children aged 9–10 years from becoming overweight or obese. The study involved 32 primary schools from Devon, half of which were randomly selected to receive the programme while the other half continued as usual. We also asked what they understood about a healthy lifestyle and how they felt about it. The study began when the children were 9–10 years old, in Year 5, and HeLP was delivered in the spring and summer terms of Year 5 and in the autumn term of Year 6. Children had their final set of measurements taken when they were at secondary school (aged 11–12 years). We were able to follow up 94% of children for their final set of measurements, an exceptionally high follow-up rate; we think that this is because schools, children and families helped us design the trial. There was no difference in the amount of physical activity children did or in the amount of time they spent not being active. We saw a positive difference in some snacking behaviours, with children who had taken part in HeLP eating fewer unhealthy snacks and having less unhealthy foods generally. Given that the programme failed to achieve sufficient change in behaviour to prevent overweight or obesity, we think that new approaches are needed to support families and children in making healthy lifestyle choices. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals xxiii provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. The intervention was developed using intervention mapping (involving extensive stakeholder involvement) and was guided by the information, motivation and behavioural skills (IMB) model. The intervention has four phases and runs over three school terms with 9- to 10-year-old children. HeLP aims to engage children, parents and schools through a mixture of educational activities, drama, goal-setting and reinforcement activities to help children to increase healthy behaviours and reduce the risk of overweight and obesity. Objectives To estimate the effectiveness and cost-effectiveness of HeLP in preventing overweight and obesity in children. To assess the effectiveness of HeLP in children aged 9–10 years by comparing between intervention and control schools: ¢ body mass index (BMI) standard deviation score (SDS) at 24 months (primary outcome) ¢ BMI SDS at 18 months ¢ waist circumference SDS at 18 and 24 months ¢ percentage body fat SDS at 18 and 24 months ¢ proportion of children classified as underweight, overweight and obese at 18 and 24 months ¢ physical activity [time, in average minutes per day, spent in sedentary, light, moderate, moderate to vigorous or vigorous physical activity, and the average volume of physical activity in milligravity (mg) units] at 18 months ¢ food intake (number of energy-dense snacks, healthy snacks, negative and positive food markers) at 18 months. To estimate the costs associated with the delivery of the HeLP intervention and its cost-effectiveness versus usual practice. To conduct a mixed-methods process evaluation and a mediational analysis to explore the way in which the programme worked (i. Methods We undertook a cluster randomised controlled trial with follow-up at 18 and 24 months post baseline (6 and 12 months post intervention) in 32 primary schools in Devon that had at least 20 pupils in Year 5 (aged 9–10 years). We aimed to recruit half of the schools with ≥ 19% pupils eligible for free school meals (the national average in 2012). Schools were randomised post collection of baseline measures. Schools allocated to receive HeLP started the programme in the spring term of Year 5 with phase 1 activities to create a receptive context in the school and to engage the children and their families. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals xxv provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. SCIENTIFIC SUMMARY activities (phase 4) took place in the autumn term of Year 5. Schools allocated to the control group continued with their standard syllabus.

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