Introdução: A Estimulação Transcraniana por Corrente Contínua (ETCC) é uma intervenção não farmacológica com resultados discordantes quanto à sua eficácia para o tratamento do Episódio Depressivo Maior (EDM). Possivelmente devido a heterogeneidade dos estudos, as três meta-análises publicadas até agora sobre o assunto apontam para uma pequena vantagem a favor da técnica, dependendo da variável de desfecho analisada (melhora de depressão ou resposta). Todas essas meta-análises utilizaram dados agregados. Focamo-nos, no presente estudo, na realização de uma revisão sistemática da literatura e de uma meta-análise baseada em dados individuais de pacientes (MA-DIP) com Depressão Maior (DM) submetidos à ETCC na fase aguda. Este tipo de análise é mais preciso na avaliação da eficácia de uma intervenção e na obtenção dos preditores de respostas de tratamento, já que as características individuais de cada sujeito são consideradas ao invés das médias e frequências, como nas meta-análises de dados agregados. Objetivos: (1) avaliar a eficácia da ETCC na fase aguda da DM, (2) identificar preditores de resposta, remissão e melhora da depressão específicos e (3) avaliar a aceitabilidade da intervenção. Resultados: Os dados foram colecionados de 6 ensaios clínicos randomizados placebo controlados, totalizando 289 sujeitos. A ETCC ativa foi estatisticamente superior à estimulação simulada em relação à resposta (34% vs. 19%, respectivamente; RC=2,44, IC 95% = 1,38-4,32, NNT=7), remissão (23,1% vs. 12,7%, respectivamente; RC= 2,38, IC 95% = 1,22 - 4,64, NNT=9) e melhora da depressão (coeficiente = 0,35, IC 95% =0,12 0,57). Demonstrou-se que após ajustes para outros preditores e confundidores, depressão resistente a tratamento e doses mais altas de ETCC foram, respectivamente, inversa e diretamente associadas com a eficácia da ETCC. Conclusões: O tamanho de efeito do tratamento com ETCC foi comparável àqueles reportados, em outros estudos, para a Estimulação Magnética Transcraniana repetitiva (EMTr) e para o tratamento farmacológico (com antidepressivos tricíclicos e inibidores seletivos de recaptação de serotonina) na atenção primária para depressão. Os parâmetros mais importantes para otimização em ensaios clínicos futuros são a refratariedade da depressão e a dose da ETCC / Introduction: Transcranial direct current stimulation (tDCS) is a nonpharmacological intervention for depression. Randomised, sham-controlled clinical trials (RCTs) conducted hitherto have presented mixed results regarding its efficacy. Although recent meta-analyses suggest some efficacy when measuring depression symptoms using a continuous outcome, these meta-analyses were limited in their results as they used an aggregate data approach. We aimed therefore to perform an individual patient data (IPD) meta-analysis. In contrast to an aggregate data meta-analysis, an IPD approach uses the raw data of each participant within a study. IPD is more accurate in estimating the efficacy of an intervention since aggregate data meta-analyses present only summary estimates of efficacy. IPD meta-analysis is also superior to the aggregate data approach for obtaining predictors of treatment outcome, as the characteristics of each patient are assessed instead of the mean and frequency values obtained in the traditional aggregate data meta-analysis. Objectives (a) To provide precise estimates of tDCS efficacy based on continuous (depression improvement) and categorical (response and remission rates) outcomes, (b) to identify variables associated with tDCS efficacy and (c) to estimate the treatment acceptability. Results: Data were gathered from six randomised sham-controlled trials, enrolling 289 patients. Active tDCS was significantly superior to sham for response (34% v. 19%, respectively, odds ratio (OR) = 2.44, 95% CI 1.384.32, number needed to treat (NNT) = 7), remission (23.1% v. 12.7%, respectively, OR = 2.38, 95% CI 1.224.64, NNT = 9) and depression improvement ( coefficient 0.35, 95% CI 0.120.57). Mixed effects models showed that, after adjustment for other predictors and confounders, treatment-resistant depression and higher tDCS doses were, respectively, negatively and positively associated with tDCS efficacy. Conclusions: The effect size of tDCS treatment was comparable with those reported for repetitive transcranial magnetic stimulation (rTMS) and antidepressant drug treatment in primary care. The most important parameters for optimisation in future trials are depression refractoriness and tDCS dose

Introdução: A Estimulação Transcraniana por Corrente Contínua (ETCC) é uma intervenção não farmacológica com resultados discordantes quanto à sua eficácia para o tratamento do Episódio Depressivo Maior (EDM). Possivelmente devido a heterogeneidade dos estudos, as três meta-análises publicadas até agora sobre o assunto apontam para uma pequena vantagem a favor da técnica, dependendo da variável de desfecho analisada (melhora de depressão ou resposta). Todas essas meta-análises utilizaram dados agregados. Focamo-nos, no presente estudo, na realização de uma revisão sistemática da literatura e de uma meta-análise baseada em dados individuais de pacientes (MA-DIP) com Depressão Maior (DM) submetidos à ETCC na fase aguda. Este tipo de análise é mais preciso na avaliação da eficácia de uma intervenção e na obtenção dos preditores de respostas de tratamento, já que as características individuais de cada sujeito são consideradas ao invés das médias e frequências, como nas meta-análises de dados agregados. Objetivos: (1) avaliar a eficácia da ETCC na fase aguda da DM, (2) identificar preditores de resposta, remissão e melhora da depressão específicos e (3) avaliar a aceitabilidade da intervenção. Resultados: Os dados foram colecionados de 6 ensaios clínicos randomizados placebo controlados, totalizando 289 sujeitos. A ETCC ativa foi estatisticamente superior à estimulação simulada em relação à resposta (34% vs. 19%, respectivamente; RC=2,44, IC 95% = 1,38-4,32, NNT=7), remissão (23,1% vs. 12,7%, respectivamente; RC= 2,38, IC 95% = 1,22 - 4,64, NNT=9) e melhora da depressão (coeficiente = 0,35, IC 95% =0,12 0,57). Demonstrou-se que após ajustes para outros preditores e confundidores, depressão resistente a tratamento e doses mais altas de ETCC foram, respectivamente, inversa e diretamente associadas com a eficácia da ETCC. Conclusões: O tamanho de efeito do tratamento com ETCC foi comparável àqueles reportados, em outros estudos, para a Estimulação Magnética Transcraniana repetitiva (EMTr) e para o tratamento farmacológico (com antidepressivos tricíclicos e inibidores seletivos de recaptação de serotonina) na atenção primária para depressão. Os parâmetros mais importantes para otimização em ensaios clínicos futuros são a refratariedade da depressão e a dose da ETCC / Introduction: Transcranial direct current stimulation (tDCS) is a nonpharmacological intervention for depression. Randomised, sham-controlled clinical trials (RCTs) conducted hitherto have presented mixed results regarding its efficacy. Although recent meta-analyses suggest some efficacy when measuring depression symptoms using a continuous outcome, these meta-analyses were limited in their results as they used an aggregate data approach. We aimed therefore to perform an individual patient data (IPD) meta-analysis. In contrast to an aggregate data meta-analysis, an IPD approach uses the raw data of each participant within a study. IPD is more accurate in estimating the efficacy of an intervention since aggregate data meta-analyses present only summary estimates of efficacy. IPD meta-analysis is also superior to the aggregate data approach for obtaining predictors of treatment outcome, as the characteristics of each patient are assessed instead of the mean and frequency values obtained in the traditional aggregate data meta-analysis. Objectives (a) To provide precise estimates of tDCS efficacy based on continuous (depression improvement) and categorical (response and remission rates) outcomes, (b) to identify variables associated with tDCS efficacy and (c) to estimate the treatment acceptability. Results: Data were gathered from six randomised sham-controlled trials, enrolling 289 patients. Active tDCS was significantly superior to sham for response (34% v. 19%, respectively, odds ratio (OR) = 2.44, 95% CI 1.384.32, number needed to treat (NNT) = 7), remission (23.1% v. 12.7%, respectively, OR = 2.38, 95% CI 1.224.64, NNT = 9) and depression improvement ( coefficient 0.35, 95% CI 0.120.57). Mixed effects models showed that, after adjustment for other predictors and confounders, treatment-resistant depression and higher tDCS doses were, respectively, negatively and positively associated with tDCS efficacy. Conclusions: The effect size of tDCS treatment was comparable with those reported for repetitive transcranial magnetic stimulation (rTMS) and antidepressant drug treatment in primary care. The most important parameters for optimisation in future trials are depression refractoriness and tDCS dose

Internet-based cognitive behavior therapy (ICBT) has the potential of providing many patients with an effective form of psychological treatment. However, despite helping to improve mental health and well-being, far from everyone seem to benefit. In some cases, negative effects may also emerge. The overall aim of the present thesis was to establish the occurrence and characteristics of such incidents in ICBT using a combination of quantitative and qualitative methods. Study I determined deterioration, non-response, and adverse and unwanted events in a sample of 133 patients undergoing ICBT for social anxiety disorder. The results indicated that up to 6.8% fared worse during the treatment period, depending on the self-report measure and time point, as determined using the Reliable Change Index (RCI), while the non-response rate was between 29.3 to 86.5% at post treatment assessment, and 12.9% experienced other negative effects. Study II investigated the responses to open-ended questions on adverse and unwanted events among 556 patients in four separate clinical trials of ICBT; social anxiety disorder, panic disorder, major depressive disorder, and procrastination. In total, 9.3% reported negative effects, with a qualitative content analysis revealing two categories and four subcategories; patient-related, i.e., gaining insight and experiencing new symptoms, and treatment-related, i.e., difficulties applying the treatment interventions and problems related to the treatment format. Study III explored the number of patients achieving reliable deterioration, as determined using the RCI on the individual raw scores of 2866 patients from 29 clinical trials of ICBT. The results showed that the deterioration rate was higher among patients in a control condition, 17.4%, in comparison to treatment, 5.8%. Predictors were related to decreased odds of deterioration for patients receiving treatment; clinical severity at pre treatment assessment, being in a relationship, having a university degree, and being older. As for the control condition, only clinical severity at pre treatment assessment was associated with decreased odds of deterioration. Study IV examined a newly developed self-report measure for monitoring and reporting adverse and unwanted events, the Negative Effects Questionnaire. The results suggested a six-factor solution with 32 items; symptoms, quality, dependency, stigma, hopelessness, and failure. One-third of the patients reported experiencing unpleasant memories, stress, and anxiety, with novel symptoms and a lack of quality in the treatment and therapeutic relationship having the greatest negative impact. The general finding of the present thesis is that negative effects do occur in ICBT and that they are characterized by deterioration, non-response, and adverse and unwanted events, similar to psychological treatments delivered face-to-face. Researchers and clinicians in ICBT are recommended to monitor and report negative effects to prevent a negative treatment trend and further the understanding of what might contribute to their incidents. Future research should investigate the relationship between negative effects and treatment outcome, especially at follow-up, to examine if they are transient or enduring. Also, interviews could be conducted with those achieving reliable deterioration to explore if and how it is experienced by the patients and to see if it is attributed to the treatment interventions or other circumstances. / Internetbaserad kognitiv beteendeterapi (IKBT) har goda förutsättningar att kunna bli en form av psykologisk behandling som på ett effektivt sätt hjälper patienter med att hantera sin psykiska ohälsa och förbättra sitt välmående. Trots detta är det dock långtifrån alla som tycks bli bättre. För en del kan det till och med resultera i negativa effekter. Det övergripande syftet med denna avhandling har således varit att undersöka förekomsten av sådana fall och hur dessa uttrycks, såväl med kvantitativa som kvalitativa metoder. Studie I fastställde andelen försämrade, oförändrade samt andra ogynnsamma eller oönskade händelser bland 133 personer som behandlades med IKBT för social ångest. Resultatet visade att uppemot 6,8 % försämrades under sin behandlingsperiod beroende på vilket självskattningsformulär respektive tidpunkt som studerades, beräknat enligt metoden Reliable Change Index (RCI). Likaså var 29,3 % till 86,5 % oförändrade vid eftermätningen samt att 12,9 % rapporterade andra former av negativa effekter. Studie II undersökte svaren på öppna frågor som gällde ogynnsamma eller oönskade händelser bland 556 patienter i fyra olika kliniska studier med IKBT; social ångest, paniksyndrom, egentlig depressionsepisod och prokrastinering. Totalt sett rapporterade 9,3 % att de hade erfarit negativa effekter, vilka analyserades med hjälp av kvalitativ innehållsanalys. Två övergripande kategorier och fyra subkategorier framkom; patientrelaterade, som ökad insikt respektive nya symptom, samt behandlingsrelaterade, som svårigheter att implementera behandlingsinterventionerna respektive problem med behandlingsformatet. Studie III utrönte andelen patienter som försämrades i enlighet med RCI, baserat på insamlad rådata från 2866 personer i 29 olika kliniska studier med IKBT. Resultatet visade att försämring var mer förekommande hos de som var i en kontrollgrupp, 17,4 %, jämfört med de som fick behandling, 5,8 %. Bland de som genomgick behandling existerade det även ett par prediktorer som innebar lägre odds för försämring; större svårigheter vid förmätningen, att befinna sig i en relation, att ha en universitetsutbildning respektive att vara äldre. För de som var i en kontrollgrupp var enbart större svårigheter vid förmätningen relaterat till lägre odds för försämring. Studie IV testade ett nykonstruerat självskattningsformulär; Negative Effects Questionnaire. Resultatet visade på en faktorlösning med sex faktorer och 32 påståenden; symptom, kvalitet, beroende, stigma, hopplöshet respektive misslyckande. En tredjedel av personerna svarade att de hade upplevt obehagliga minnen, stress och ångest, samtidigt som nya symptom och bristande kvalitet i både behandlingen respektive den terapeutiska relationen hade haft störst negativ inverkan på dem. Den generella slutsatsen av denna avhandling är således att negativa effekter förekommer i IKBT och att de kännetecknas av försämring, ett oförändrat tillstånd samt andra ogynnsamma eller oönskade händelser, något som liknar tidigare forskning av psykologisk behandling som bedrivs ansikte-mot-ansikte. Forskare och behandlare i IKBT rekommenderas att övervaka och rapportera negativa effekter i syfte att förhindra en negativ utveckling i behandlingen samt för att öka kunskapen om vad som kan bidra till deras förekomst. Framtida forskning bör undersöka relationen mellan negativa effekter och behandlingsutfall utifrån längre tidsperspektiv för att se om dess påverkan är övergående eller ihållande. Vidare kan till exempel intervjuer utföras med de patienter som har försämrats för att ta reda på om och hur det uppfattas samt huruvida det har förorsakats av behandlingen eller andra omständigheter. / <p>At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: In press.</p>