Quantitative assessment of the pharmacotherapy of biopolar disorder and schizophrenia

The work present in this thesis was aimed at assessing the efficacy of lithium in the acute treatment of mania and for the prophylaxis of bipolar disorder, and investigating the value of plasma haloperidol concentration for predicting response to treatment in schizophrenia. The pharmacogenetics of psychotropic drugs is critically appraised to provide insights into interindividual variability in response to pharmacotherapy, In clinical trials of acute mania, a number of measures have been used to assess the severity of illness and its response to treatment. Rating instruments need to be validated in order for a clinical study to provide reliable and meaningful estimates of treatment effects, Eight symptom-rating scales were identified and critically assessed, The Mania Rating Scale (MRS) was the most commonly used for assessing treatment response, The advantage of the MRS is that there is a relatively extensive database of studies based on it and this will no doubt ensure that it remains a gold standard for the foreseeable future. Other useful rating scales are available for measuring mania but further cross-validation and validation against clinically meaningful global changes are required. A total of 658 patients from 12 trials were included in an evaluation of the efficacy of lithium in the treatment of acute mania. Treatment periods ranged from 3 to 4 weeks. Efficacy was estimated using (i) the differences in the reduction in mania severity scores, and (ii) the ratio and difference in improvement response rates. The response rate ratio for lithium against placebo was 1.95 (95% CI 1.17 to 3.23). The mean number needed to treat was 5 (95% CI 3 to 20). Patients were twice as likely to obtain remission with lithium than with chlorpromazine (rate ratio = 1.96, 95% CI 1.02 to 3.77). The mean number needed to treat (NNT) was 4 (95% CI 3 to 9). Neither carbamazepine nor valproate was more effective than lithium. The response rate ratios were 1.01 (95% CI 0.54 to 1.88) for lithium compared to carbarnazepine and 1.22 (95% CI 0.91 to 1.64) for lithium against valproate. Haloperidol was no better than lithium on the basis of improvement based on assessment of global severity. The differences in effects between lithium and risperidone were -2.79 (95% CI -4.22 to -1.36) in favour of risperidone with respect to symptom severity improvement and -0.76 (95% CI -1.11 to -0,41) on the basis of reduction in global severity of disease. Symptom and global severity was at least as well controlIed with lithium as with verapamil. Lithium caused more side-effects than placebo and verapamil, but no more than carbamazepine or valproate. A total of 554 patients from 13 trials were included in the statistical analysis of lithium's efficacy in the prophylaxis of bipolar disorder. The mean follow-up period was 5-34 months. The relapse risk ratio for lithium versus placebo was 0.47 (95% CI 0.26 to 0.86) and the NNT was 3 (95% CI 2 to 7). The relapse risk ratio for lithium versus imipramine was 0.62 (95% CI 0.46 to 0.84) and the NNT was 4 (951% Cl 3 to 7), The combination of lithium and imipramine was no more effective than lithium alone. The risk of relapse was greater with lithium alone than with the lithium-divalproate combination. A risk difference of 0.60 (95% CI 0.21 to 0.99) and an NNT of 2 (95% CI 1 to 5) were obtained. Lithium was as effective as carbamazepine. Based on individual data concerning plasma haloperidol concentration and percent improvement in psychotic symptoms, our results suggest an acceptable concentration range of 11.20-30.30 ng/mL A minimum of 2 weeks should be allowed before evaluating therapeutic response. Monitoring of drug plasma levels seems not to be necessary unless behavioural toxicity or noncompliance is suspected. Pharmacokinetics and pharmacodynamics, which are mainly determined by genetic factors, contribute to interindividual and interethnic variations in clinical response to drugs. These variations are primarily due to differences in drug metabolism. Variability in pharmacokinetics of a number of drugs is associated with oxidation polymorphism. Debrisoquine/sparteine hydroxylase (CYP2D6) and the S-mephenytoin hydroxylase (CYP2C19) are polymorphic P450 enzymes with particular importance in psychopharmacotherapy. The enzymes are responsible for the metabolism of many commonly used antipsychotic and antidepressant drugs. The incidence of poor metabolisers of debrisoquine and S-mephenytoin varies widely among populations. Ethnic variations in polymorphic isoenzymes may, at least in part, explain ethnic differences in response to pharmacotherapy of antipsychotics and antidepressant drugs.

Statnote 5: Is one set of data more variable than another?

There may be circumstances where it is necessary for microbiologists to compare variances rather than means, e,g., in analysing data from experiments to determine whether a particular treatment alters the degree of variability or testing the assumption of homogeneity of variance prior to other statistical tests. All of the tests described in this Statnote have their limitations. Bartlett’s test may be too sensitive but Levene’s and the Brown-Forsythe tests also have problems. We would recommend the use of the variance-ratio test to compare two variances and the careful application of Bartlett’s test if there are more than two groups. Considering that these tests are not particularly robust, it should be remembered that the homogeneity of variance assumption is usually the least important of those considered when carrying out an ANOVA. If there is concern about this assumption and especially if the other assumptions of the analysis are also not likely to be met, e.g., lack of normality or non additivity of treatment effects then it may be better either to transform the data or to carry out a non-parametric test on the data.

Data analysis methods in optometry. Part 5: correlation

1. Pearson's correlation coefficient only tests whether the data fit a linear model. With large numbers of observations, quite small values of r become significant and the X variable may only account for a minute proportion of the variance in Y. Hence, the value of r squared should always be calculated and included in a discussion of the significance of r. 2. The use of r assumes that a bivariate normal distribution is present and this assumption should be examined prior to the study. If Pearson's r is not appropriate, then a non-parametric correlation coefficient such as Spearman's rs may be used. 3. A significant correlation should not be interpreted as indicating causation especially in observational studies in which there is a high probability that the two variables are correlated because of their mutual correlations with other variables. 4. In studies of measurement error, there are problems in using r as a test of reliability and the ‘intra-class correlation coefficient’ should be used as an alternative. A correlation test provides only limited information as to the relationship between two variables. Fitting a regression line to the data using the method known as ‘least square’ provides much more information and the methods of regression and their application in optometry will be discussed in the next article.

Ranibizumab 0.5 mg for diabetic macular edema with bimonthly monitoring after a phase of initial treatment:18-month, multicenter, phase IIIB RELIGHT study

Abstract PURPOSE: To evaluate ranibizumab 0.5 mg using bimonthly monitoring and individualized re-treatment after monthly follow-up for 6 months in patients with visual impairment due to diabetic macular edema (DME). DESIGN: A phase IIIb, 18-month, prospective, open-label, multicenter, single-arm study in the United Kingdom. PARTICIPANTS: Participants (N = 109) with visual impairment due to DME. METHODS: Participants received 3 initial monthly ranibizumab 0.5 mg injections (day 0 to month 2), followed by individualized best-corrected visual acuity (BCVA) and optical coherence tomography-guided re-treatment with monthly (months 3-5) and subsequent bimonthly follow-up (months 6-18). Laser was allowed after month 6. MAIN OUTCOME MEASURES: Mean change in BCVA from baseline to month 12 (primary end point), mean change in BCVA and central retinal thickness (CRT) from baseline to month 18, gain of ≥10 and ≥15 letters, treatment exposure, and incidence of adverse events over 18 months. RESULTS: Of 109 participants, 100 (91.7%) and 99 (90.8%) completed the 12 and 18 months of the study, respectively. The mean age was 63.7 years, the mean duration of DME was 40 months, and 77.1% of the participants had received prior laser treatment (study eye). At baseline, mean BCVA was 62.9 letters, 20% of patients had a baseline BCVA of >73 letters, and mean baseline CRT was 418.1 μm, with 32% of patients having a baseline CRT <300 μm. The mean change in BCVA from baseline to month 6 was +6.6 letters (95% confidence interval [CI], 4.9-8.3), and after institution of bimonthly treatment the mean change in BCVA at month 12 was +4.8 letters (95% CI, 2.9-6.7; P < 0.001) and +6.5 letters (95% CI, 4.2-8.8) at month 18. The proportion of participants gaining ≥10 and ≥15 letters was 24.8% and 13.8% at month 12 and 34.9% and 19.3% at month 18, respectively. Participants received a mean of 6.8 and 8.5 injections over 12 and 18 months, respectively. No new ocular or nonocular safety findings were observed during the study. CONCLUSIONS: The BCVA gain achieved in the initial 6-month treatment period was maintained with an additional 12 months of bimonthly ranibizumab PRN treatment.

[Review of] Ivo Mijnssen, The Quest for an Ideal Youth in Putin’s Russia I. Back to Our Future! History, Modernity and Patriotism According to Nashi, 2005–2012. Soviet and Post-Soviet Politics and Society, Stuttgart: Ibidem Verlag, 2012, 202pp., e 34.90 p/b

THE YOUTH MOVEMENT NASHI (OURS) WAS FOUNDED IN THE SPRING of 2005 against the backdrop of Ukraine’s ‘Orange Revolution’. Its aim was to stabilise Russia’s political system and take back the streets from opposition demonstrators. Personally loyal to Putin and taking its ideological orientation from Surkov’s concept of ‘sovereign democracy’, Nashi has sought to turn the tide on ‘defeatism’ and develop Russian youth into a patriotic new elite that ‘believes in the future of Russia’ (p. 15). Combining a wealth of empirical detail and the application of insights from discourse theory, Ivo Mijnssen analyses the organisation’s development between 2005 and 2012. His analysis focuses on three key moments—the organisation’s foundation, the apogee of its mobilisation around the Bronze Soldier dispute with Estonia, and the 2010 Seliger youth camp—to help understand Nashi’s organisation, purpose and ideational outlook as well as the limitations and challenges it faces. As such,the book is insightful both for those with an interest in post-Soviet Russian youth culture, and for scholars seeking a rounded understanding of the Kremlin’s initiatives to return a sense of identity and purpose to Russian national life.The first chapter, ‘Background and Context’, outlines the conceptual toolkit provided by Ernesto Laclau and Chantal Mouffe to help make sense of developments on the terrain of identity politics. In their terms, since the collapse of the Soviet Union, Russia has experienced acute dislocation of its identity. With the tangible loss of great power status, Russian realities have become unfixed from a discourse enabling national life to be constructed, albeit inherently contingently, as meaningful. The lack of a Gramscian hegemonic discourse to provide a unifying national idea was securitised as an existential threat demanding special measures. Accordingly, the identification of those who are ‘notUs’ has been a recurrent theme of Nashi’s discourse and activity. With the victory in World War II held up as a foundational moment, a constitutive other is found in the notion of ‘unusual fascists’. This notion includes not just neo-Nazis, but reflects a chain of equivalence that expands to include a range of perceived enemies of Putin’s consolidation project such as oligarchs and pro-Western liberals.The empirical background is provided by the second chapter, ‘Russia’s Youth, the Orange Revolution, and Nashi’, which traces the emergence of Nashi amid the climate of political instability of 2004 and 2005. A particularly note-worthy aspect of Mijnssen’s work is the inclusion of citations from his interviews with Nashicommissars; the youth movement’s cadres. Although relatively few in number, such insider conversations provide insight into the ethos of Nashi’s organisation and the outlook of those who have pledged their involvement. Besides the discussion of Nashi’s manifesto, the reader thus gains insight into the motivations of some participants and behind-the-scenes details of Nashi’s activities in response to the perceived threat of anti-government protests. The third chapter, ‘Nashi’s Bronze Soldier’, charts Nashi’s role in elevating the removal of a World War II monument from downtown Tallinn into an international dispute over the interpretation of history. The events subsequent to this securitisation of memory are charted in detail, concluding that Nashi’s activities were ultimately unsuccessful as their demands received little official support.The fourth chapter, ‘Seliger: The Foundry of Modernisation’, presents a distinctive feature of Mijnssen’s study, namely his ethnographic account as a participant observer in the Youth International Forum at Seliger. In the early years of the camp (2005–2007), Russian participants received extensive training, including master classes in ‘methods of forestalling mass unrest’ (p. 131), and the camp served to foster a sense of group identity and purpose among activists. After 2009 the event was no longer officially run as a Nashi camp, and its role became that of a forum for the exchange of ideas about innovation, although camp spirit remained a central feature. In 2010 the camp welcomed international attendees for the first time. As one of about 700 international participants in that year the author provides a fascinating account based on fieldwork diaries.Despite the polemical nature of the topic, Mijnssen’s analysis remains even-handed, exemplified in his balanced assessment of the Seliger experience. While he details the frustrations and disappointments of the international participants with regard to the unaccustomed strict camp discipline, organisational and communication failures, and the controlled format of many discussions,he does not neglect to note the camp’s successes in generating a gratifying collective dynamic between the participants, even among the international attendees who spent only a week there.In addition to the useful bibliography, the book is back-ended by two appendices, which provide the reader with important Russian-language primary source materials. The first is Nashi’s ‘Unusual Fascism’ (Neobyknovennyi fashizm) brochure, and the second is the booklet entitled ‘Some Uncomfortable Questions to the Russian Authorities’ (Neskol’ko neudobnykh voprosov rossiiskoivlasti) which was provided to the Seliger 2010 instructors to guide them in responding to probing questions from foreign participants. Given that these are not readily publicly available even now, they constitute a useful resource from the historical perspective.

Flat-top supercontinuum and tunable femtosecond fiber laser sources at 1.9-2.5 μm

We report the high-energy flat-top supercontinuum covering the mid-infrared wavelength range of 1.9-2.5 μm as well as electronically tunable femtosecond pulses between 1.98-2.22 μm directly from the thulium-doped fiber laser amplifier. Comparison of experimental results with numerical simulations confirms that both sources employ the same nonlinear optical mechanism - Raman soliton frequency shift occurring inside the Tm-fiber amplifier. To illustrate that, we investigate two versions of the compact diode-pumped SESAM mode-locked femtosecond thulium-doped all-silica-fiber-based laser system providing either broadband supercontinuum or tunable Raman soliton output, depending on the parameters of the system. The first system operates in the Raman soliton regime providing femtosecond pulses tunable between 1.98-2.22 μm. Wide and continuous spectral tunability over 240 nm was realized by changing only the amplifier pump diode current. The second system generates high-energy supercontinuum with the superior spectral flatness of better than 1 dB covering the wavelength range of 1.9-2.5 μm, with the total output energy as high as 0.284 μJ, the average power of 2.1 W at 7.5 MHz repetition rate. We simulate the amplifier operation in the Raman soliton self-frequency shift regime and discuss the role of induced Raman scattering in supercontinuum formation inside the fiber amplifier. We compare this system with a more traditional 1.85-2.53 μm supercontinuum source in the external highly-nonlinear commercial chalcogenide fiber using the Raman soliton MOPA as an excitation source. The reported systems1 can be readily applied to a number of industrial applications in the mid-IR, including sensing, stand-off detection, medical surgery and fine material processing.