Therapeutics, Pharmacology and Clinical Toxicology
D. Vasile1, O. Vasiliu2, A. G. Mangalagiu2, Diana Gabriela Ojog1
1. University of Medicine and Pharmacy “Carol Davila,” Bucharest 2. Military Emergency Universitary Hospital “Dr. Carol Davila” Bucharest, Department of Psychiatry Abstract. The efficacy of selective serotonin reuptake inhibitors (SSRIs) in the treatment of obsessive-
compulsive disorder (OCD) has some important limitations, as almost half of these patients are non- responders. Therefore, an increasing number of pharmacological augmentation strategies have been developed in order to cope with SSRIs non-responders: increasing dosages to the maximum tolerated level, antidepressants switch, augmentation with pharmacologic agents or psychotherapy, alternative ways of treatment administration etc. In this systematic review we evaluated studies which focused upon the efficacy of the pharmacologic augmentation strategies in SSRIs resistant cases of OCD. Atypical and typi- cal antipsychotics, antidepressants and other agents such as beta-blockers, psychostimulants or omega 3 fatty acids were detected in clinical studies and included in our review. The most supported strategies are typical antipsychotics (especially haloperidol), atypical antipsychotics (mainly risperidone), antidepres- sants like clomipramine or trazodone and the beta-blocker pindolol. More research is needed in order to evaluate the efficacy of other pharmacologic agents, such as newer antipsychotics and antidepressants, mood-stabilizers and various serotoninergic agents.
Keywords: resistant obsessive-compulsive disorder, antidepressants, antipsychotics, mood-stabilizers,
1. Introduction
patients fail to respond to first-line medications [2].
Although clomipramine and selective sero- The efficacy of increased antidepressant (mainly tonin reuptake inhibitors (SSRIs) efficacy in SSRIs) dosages for resistant OCD was evaluated in obsessive-compulsive disorder (OCD) is sustained both prospective [3,4] and retrospective trials [5] by many researches in the literature, this pathology with favourable results. Doses of sertraline were is associated with a notorious tendency to treat- increased up to 400 mg daily and escitalopram was ment- refractoriness and a rather reserved long-term administered in 33.8 mg mean daily dose. Stil , the prognosis. It is estimated that more than 40-60% of dangers of adverse events and lowering the quality the SSRIs treated population have negative results of patients’ life suggest the need for investigating that are associated with serious social disability [1]. This situation is not singular in the anxiety disor- Intravenous administration of clomipramine was ders spectrum, as a Cochrane meta-analysis (28 evaluated in a smal scale RCT in patients refractory short-term randomized control ed trials-RCTs, 740 to oral clomipramine and the results were superior participants) showed that a significant proportion of to placebo [6]. There is a lack of replication studies regarding this specific technique, so its efficacy is Daniel Vasile MD, PhD
Antidepressant switch is an option whenever Military Emergency Universitary Hospital “Dr. Carol adverse events are severe or the drug efficacy after Davila” Bucharest, Department of Psychiatry 8-10 weeks at the high-end of the therapeutic range is not satisfactory. The duration of a therapeutic trial in OCD is extended by many authors to 12 Augmentation strategies in resistant obsessive-compulsive disorder weeks, due to the peculiarities of this disorder [7]. not respond to treatment. We did not include trials Although this recommendation is intuitive and with psychotherapy and pharmacotherapy combos, frequently used in clinical practice, there are few this decision being based upon the need for a more studies evaluating long-term efficacy of this strategy. homogenous group of therapeutic strategies.
Clinicians could switch to a different antidepressant, We included in our review al the drugs found cognitive-behavioral therapy or, less frequently, to as augmentation pharmacologic agents, even the dietary supplements or over the counter medicines. Criteria
Population with age over 18, diagnosed Trials with unspecified age of the target popula- Patients who had not previously received SSRIs.
Patients that received augmentation pharmaco- Intervention
CTs with psychotherapy or combined psycho- Hospital, day-care, ambulatory settings Unspecified place of intervention Decreasing the severity of OCD as CTs without decreasing the severity of OCD main outcome (evaluated on clinical symptoms as main outcome. increases in the quality of life, general Table 1. Overview of inclusion/exclusion criteria for the systematic literature review
2. Objective and methods
3. Results
Augmentation in resistant OCD is the mostly A number of 67 studies or reviews were found, researched strategy and the majority of data support but only 44 researches satisfied the criteria for the utility of this approach. Therefore, we selected inclusion in this review. Since all the studies, as main objective of our review the augmentation meta-analyses and systematic reviews are indexed strategies efficacy. For this purpose we selected clini- and could be consulted in the references list, we cal studies through a search in PubMed, MEDLINE included in the summary table only the most im- and Cochrane databases, recorded until September 2010 and reference list of articles. We selected stud- ies corresponding to keywords “resistant obsessive 3.1. Typical antipsychotics
compulsive disorder”, “augmentation” and “pharma- The first double-blind, placebo-control ed an- cological treatment”. Al the studies were performed tipsychotic augmentation of serotonergic therapy on adult population, using at least two different in patients with obsessive-compulsive disorder drugs simultaneously, with the second pharmaco- resistant to treatment, included 34 subjects in logic agent being introduced after at least 8 weeks the fluvoxamine nonresponders [8]. Patients were of mono-therapy with unsatisfactory results (partial randomly assigned to haloperidol (2-10 mg/day, n or complete non-responsiveness). Al patients were = 17) or placebo (n = 17) and monitored for four diagnosed with DSM IV TR/DSM IV/DSM III R weeks. Of the subjects who received haloperidol criteria of OCD and presented at least one previ- group 11 were responders, compared with none in ous trial with an SSRI during which patients did the placebo group. Responsiveness was defined by Therapeutics, Pharmacology and Clinical Toxicology score, clinician consensus Response defined as YBO Augmentation strategies in resistant obsessive-compulsive disorder in patients w 3 m tolerated SRI therapy. aloperidol, risperidone- suffi quetiapine group vs. 1.8+/- 3.4 (7% group (F=16.99, df=1.38, p<0.001); 8 responders in the quetiapine group vs. 2 in placebo group (chi quetiapine and olanzapine- inconclusive evidence 2. score
wi responders to SRI m therapy or SRI com Therapeutics, Pharmacology and Clinical Toxicology Y-BOCS the score with 35% and score under 16, symptoms of the obsessive-compulsive disorder, as CGI-I 1.2 and clinician consensus between principal the Y-BOCS lower total score, and this tendency investigator and two other investigators. Patients to decrease was maintained throughout the 12 with comorbid tic disorder responded better to haloperidol, compared to patients without tics.
Comparison of olanzapine and risperidone
A literature review [9] showed that early studies augmentation regarding the augmentation of the of SSRIs augmentation with haloperidol or pimozide SSRI effect in OCD patients who responded by not in OCD demonstrated favourable response.
more than 35% decrease in Y-BOCS score after 16 3.2. Atypical antipsychotics
weeks was achieved in a single blind study [20], lasting 8 weeks. Patients receiving augmentation Risperidone has been evaluated in terms of ef-
therapy had significant response to the baseline ficacy and tolerability as augmentation strategy in without recording differences in the efficacy of the four open label RT [10,11,12,13] and two double- blind studies [14,15]. The results were positive for A case report on aripiprazole augmentation
risperidone, this drug proved to be superior to of SSRI therapy at high doses involved a patient placebo as an augmentation agent in OCD resis- with limited insight OCD who had a favourable tant patients with one or more failed SSRIs trials. Patients were monitored using Y-BOCS and clinical Amisulpride, in a flexible dose of 200-600 mg/
consensus. Risperidone decreased OCD symptoms, day (mean dose 325+/-106 mg/day), was evaluated but also depressive and anxiety symptoms [14].
as an augmentation strategy in 20 patients with Olanzapine was also assessed in subjects with
refractory OCD to SSRIs in an open study [22]. OCD refractory to treatment with SSRIs. A placebo- The difference between the baseline and endpoint control ed trial, double blind, [16] included 26 sub- Y-BOCS score (26.7 +/-6.3 to 12.5+ / -2.8) was jects with 6 weeks of augmentation with olanzapine statistical y significant (p = 0.0001).
(up to 20 mg/day) versus placebo. Y-BOCS covari- Quetiapine was administered in a double-blind,
ance analysis scores was used to determine effective randomized, placebo-control ed augmentation of strategies for augmentation, and responsiveness was SSRI therapy for obsessive-compulsive disorder re- defined as a decrease of at least 25% of scores on fractory to SSRIs [23]. This study used flexible doses this scale. Among patients treated with olanzapine, of quetiapine in patients who had not responded a total of six (46%) showed improvement over 25% adequately to a period of 12 weeks SSRI open-label. of Y-BOCS score, compared with no cases in the The double-blind phase included 42 patients who were randomized to placebo or quetiapine for 6 Another double-blind, placebo-control ed study weeks. There were significant improvements in the of 6-week duration, included the addition of lower recorded scores Y-BOCS, both among those treated doses of olanzapine (5-10 mg/day) with fluoxetine with quetiapine (40% responders, n = 8) and in therapy in cases resistant obsessive-compulsive patients treated with placebo (47.6% responders, disorder [17]. Patients had fol owed an open-label n = 10). Thus, quetiapine did not demonstrate phase, lasting eight weeks, which received fluox- significant benefit compared with placebo at the etine, the response was partial or absent. The end of six weeks of treatment (p =0.636).
group receiving olanzapine and fluoxetine, and one Another double-blind, randomized, placebo- that was treated with fluoxetine plus placebo had control ed trial [24] included 40 elderly patients significant improvements during the 6 weeks (F = diagnosed with primary OCD, who were assessed during 8 weeks therapy with quetiapine 300 mg/ An open-label study [18] included 10 partici- day or placebo. Al patients were non-responsive pants diagnosed with OCD for at least one year, to at least two different antidepressants in the SSRI with a minimum Y-BOCS value of 18. Patients class, administered at the maximum tolerated doses were nonresponders to fluoxetine (at least 60 mg/ for 8 weeks. Responders were defined by subtract- day, minimum 10 weeks) and had failed 1-5 trials ing Y-BOCS score at least 35%. The final results focused only on SSRIs. These subjects received as showed mean reductions of Y-BOCS score by 9.0 augmentation strategy olanzapine, in doses increas- +/-7.0 (31%) in subjects treated with quetiapine and ing from 2.5 mg/day to 10 mg/day, during 4 weeks. 1.8 +/-3.4 (7%) in the placebo group (p <0.001), 8 A long term study, open label, included 26 sub- patients who received active substance (40%) and jects with obsessive-compulsive disorder, diagnosed 2 (10%) of those receiving placebo were respond- for at least two years, resistant to SSRIs therapy, who received olanzapine and were monitored for There are also open label studies which show at least one year [19]. After 12 weeks of combina- positive results for quetiapine as an augmenting tion therapy, most patients (n = 17) had reduced agent in OCD SSRIs non-responders [25,26,27]. Augmentation strategies in resistant obsessive-compulsive disorder Ziprasidone and quetiapine were compared in
3.4. Antidepressants
a retrospective study in 24 patients, as augmenta- tion strategies with high doses of SSRIs [28]. Global Citalopram administered intravenously (iv) was
clinical improvement was obtained in 80% of the evaluated in an open study on a group comprising patients treated with quetiapine and 44.4% of those 39 outpatients diagnosed with OCD, monitored for treated with ziprasidone, the overal improvement over 3 weeks [32]. Patients included in this study on Y-BOCS being 66.7%. Y-BOCS and CGI scores had moderate to severe OCD symptoms, persist- were higher at 2, 3 and 6 months fol ow-up for ing for at least one year, a Y-BOCS original score patients in the ziprasidone group, compared with of at least 25 and they had not responded to at least two oral SSRIs trials, except for citalopram. Drug administration was performed iv, starting Comparative analysis of antipsychotics
from 20 mg/day, up to 40-80 mg/day, depending on individual tolerability, during the first 21 days A systematic review of the SSRI therapy anti- and oral y thereafter, until day 84. Study results psychotic augmentation effect in refractory OCD show that the substance was wel tolerated even at [29] included double-blind, randomized studies high doses (2.6% discontinuation rate). In terms of contained in the PubMed (1967-2005), Embase effectiveness, the Y-BOCS score decreased by 35% (1974-2000) and Cochrane Central Register of in 39 patients, of whom 4 had reductions of more Control ed Trials databases. Patients considered than 35%. Some of the patients had reductions in responsive were those with more than 35% re- the Y-BOCS total score of over 20% (n = 27) and duction in Y- BOCS scale during augmentation additional improvements were obtained by day 84.
with antipsychotics. Nine studies involving 278 Clomipramine added to SSRIs or vice versa,
participants were obtained from the search in the adding an SSRI to clomipramine, as augmentation mentioned databases. The meta-analysis of these therapy is an option supported by several open studies supported the effectiveness of antipsy- studies and expert consensus. Another open-label, chotic augmentation (absolute risk difference was comparison RT, involved citalopram vs. citalopram significant at values of 0.22, confidence interval plus clomipramine in patients with resistant to 0.13-0.31). Another finding of this meta-analysis treatment OCD [33]. This trial evaluated 16 adult was that patients with OCD should be treated with outpatients (aged between 18 and 45 years) for 90 SSRIs for at least three months at maximum dose days with moderate to severe forms of OCD, the before initiation of antipsychotic augmentation. minimum initial Y-BOCS score 25, without co- Only one third of patients with resistant OCD had a morbid axis I, who had not responded to therapy significant response to antipsychotic augmentation. with clomipramine or citalopram, administered Data from the literature supports the effectiveness separately. Patients treated with citalopram and of haloperidol, risperidone and less of quetiapine clomipramine (n=9) had a Y-BOCS score decreas- ing significantly compared with patients Y-BOCS Augmentation with atypical antipsychotics has treated only with citalopram (n=7) at day 90. The been studied in SSRIs non-responders (n=44) af- average improvement of the Y-BOCS score was ter 12 weeks that were subsequently assigned to 35% in patients who received antidepressants combination therapy with SSRIs and olanzapine, quetiapine or risperidone, in paral el with cognitive- Infused clomipramine was evaluated in 56 sub- behavioral therapy [30]. The duration of this study jects diagnosed as refractory to oral clomipramine was one year and, in terms of results, it was found OCD [34]. Clomipramine was administered to these that the Y-BOCS total score decreased from 29.3 patients as 14 infusion doses and the fol ow-up pe- +/-9.9 (baseline) to 19.3+/-6.8 (one year). riod ranged from 4 to 11 years. Of the 44 subjects Another meta-analysis focused upon the ef- interviewed on re-evaluation, 70.5% had OCD and fectiveness of antipsychotic augmentation in SRIs obsessive-compulsive symptoms, while 29.5% were refractory OCD included 10 RTs with the fol owing below the clinical level. Nearly 50% reported large active substances: haloperidol (n = 1), risperidone and very large improvements compared to their (n = 3), olanzapine (n = 2) and quetiapine (n = previous status with clomipramine infusion. 4) [31]. The total number of subjects included in In patients with inadequate response to 6 this meta-analysis was 305, out of which 157 were months of clomipramine 150 mg/day the addition randomized on pharmacological y active agent and of 50 mg/day sertraline was considered better than 148 on placebo. The response was more frequently when the dose of clomipramine was increased to observed in patients receiving antipsychotics and the combined weighted rate of responsiveness was Trazodone as a strategy for augmentation of
3.31 (95%, confidence interval 1.40-7.84). SSRI therapy was evaluated in a series of case Therapeutics, Pharmacology and Clinical Toxicology reports and smal scale studies. Thus, in some of 60 mg/day buspirone as augmentation strategy cases (n = 5), augmentation of SSRI therapy with to fluvoxamine showed negative results [45].
trazodone 300-600 mg/day has helped to reduce Inositol has been studied in double-blind, pla-
symptoms of OCD, anxiety and sleeplessness, sexual cebo-control ed studies as an augmentation strategy dysfunction and gastrointestinal discomfort [36]. A and the data suggest a mild effect of this drug in double-blind, placebo-control ed RT that included a minority of resistant obsessive-compulsive disor- 11 subjects treated with trazodone (235 mg/day der patients. One double-blind, placebo-control ed mean dose) and 6 patients who received placebo, study, with 13 subjects, evaluated the effect of found no significant differences between the two adding inositol to SSRIs and concluded that there groups [37]. However, this study was short term (6 was a smal but significant decrease in the active weeks) and included too few subjects to be relevant.
drug group [46]. Another double-blind, placebo- 3.5. Others
control ed study showed no difference between groups, but there were only 10 patients included A placebo-controlled cross-over trial used eicosapentaenoic acid (EPA) as adjunctive agent
Memantine is another drug evaluated for the
in SSRI treated obsessive-compulsive disorder [38]. treatment of resistant obsessive-compulsive dis- This study included 11 patients on stable maximal y order in a 2009 clinical trial due to the genetics, tolerated dose of SSRI with no improvement in neuroimaging, animal studies and case reports that the last 2 months. These patients were randomly support involvement of glutamatergic mechanisms al ocated on placebo (6 weeks), fol owed by 2 g in the pathophysiology of this pathology [48]. In of EPA, or EPA fol owed by placebo, while they an open-label trial 15 adult subjects who had not continued the SSRI treatment. The mean scores responded to SSRIs treatment for at least 12 weeks declined from 26.0 +/-5 to 17.6+/-6 by week 6 received 20 mg/day memantine for 12 weeks. At on placebo and to 18.5+/-4 on EPA. The negative endpoint, 6 patients were responders (42.9%) as results suggest that adjunctive EPA is not recom- mended as adjunctive agent to SSRI in resistant Topiramate is another glutamatergic drug
investigated as an augmentation agent in SSRIs Dextroamphetamine proved itself efficient
monotherapy partial or nonresponsive patients for versus placebo in severe chronic OCD in a double- a minimum of 14 weeks [49]. The mean dose of topiramate was 253.1+/-93.9 mg/day and the mean Pindolol is a beta-blocker and serotonin 1A
time to response was 9.2+/- 4.5 weeks. CGI-S scores presynaptic receptor antagonist that increases decreased significantly from initiation of topiramate serotoninergic transmission and has mixed results until 26 weeks (p<0.001). This case series sug- as augmentation agent in resistant obsessive- gests the addition of topiramate may be useful in compulsive disorder. Pindolol up to 2.5 mg x 3/ treatment-resistant obsessive-compulsive disorder. day was associated to paroxetine (60 mg daily) Gabapentin (mean dose 2520 mg/day) augmen-
in a double-blind, placebo-controlled study, in tation was evaluated in a 6 weeks open-label study resistant obsessive compulsive disorder [40]. This in 5 patients who responded partial y to fluoxetine augmentation strategy was efficient vs. placebo after [50]. This trial showed a partial response to gaba- 4 weeks (p<0.006) on Y-BOCS scores. An 8-week, double-blind, placebo-control ed study examined A double-blind, placebo-control ed study [51] the efficacy of pindolol added to fluvoxamine [41] showed a response (Y-BOCS decrease with 25%) and found no differences between active drug and to 30-45 mg once-weekly oral morphine sulphate
placebo. Two open-label studies found either a mod- est effect of pindolol augmentation (one responsive Ondansetron 1 mg x 3 times daily was associ-
patient out of 8) or response only after tryptophan ated with significant decrease in Y-BOCS scores in was also added to a serotoninergic agent, in a triple an 8 weeks, smal , open-label study [52].
Buspirone in doses up to 60 mg/day was evalu-
ated in smal and methodological y limited studies The synthesis of clinical data extracted from the that could not find certain effectiveness in resistant systematic review is presented in table 3, accompa- OCD. A 10 weeks, double blind, placebo-control ed nied by the level of evidence for each augmentation RT evaluated buspirone augmentation but did not find significant differences versus placebo, also 29% The most convincing data at this moment sup- of buspirone patients responded, as the YBOCS port augmentation of SSRIs resistant OCD with scores showed [44]. Another 6-week, double-blind, antipsychotics (level of evidence B). There are sig- placebo control ed study that evaluated the efficacy nificant differences between individual antipsychot- Augmentation strategies in resistant obsessive-compulsive disorder Class of drugs
Level of evidence
Typical antipsychotics
Atypical antipsychotics
Antipsychotics overall efficacy
(typical, atypical)
Table 3. Level of evidence for augmentation strategies in SSRIs resistant OCD
GRADE A High quality— Further research is very unlikely
to change our confidence in the estimate of effect, GRADE B Moderate quality— Further research is likely to
PC=placebo controlled, OL=open label have an important impact on our confidence in the estimate of effect and may change the estimate, GRADE C Low quality— Further research is very likely to
have an important impact on our confidence in the estimate of effect and is likely to change the estimate, GRADE D Very low quality— Any estimate of effect is
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Therapeutics, Pharmacology and Clinical Toxicology

Source: http://www.terapeutica.ro/Issues/2011/number2/pdf/R1.Vasile.pdf

Attachment 2: compendium of getting the jump

NSW NATIONAL PARKS AND WILDLIFE SERVICE Threatened Species Management Information Circular No. 6 Hygiene Protocol for the Control of Disease in Frogs NSW National Parks and Wildlife Service Acknowledgments NSW National Parks and Wildlife Service Declining Frog Working Group who recommended thepreparation and provided input into the development of this strategy. Ross Wellingto


RELAZIONE DELLA COMMISSIONE Relazione sulla politica di concorrenza 2012 INTRODUZIONE L’Unione europea (UE) è il più grande spazio economico e commerciale al mondo. Il suo mercato unico, che comprende oltre mezzo miliardo di consumatori e più di 20 milioni di imprese, costituisce una risorsa unica e un incomparabile vantaggio competitivo sulla sce

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