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Response to lithium in patients with bipolar disorder is associated with clinical and transdiagnostic genetic factors. The predictive combination of these variables might help clinicians better predict which patients will respond to lithium treatment.
To use a combination of transdiagnostic genetic and clinical factors to predict lithium response in patients with bipolar disorder.
This study utilised genetic and clinical data (n = 1034) collected as part of the International Consortium on Lithium Genetics (ConLi+Gen) project. Polygenic risk scores (PRS) were computed for schizophrenia and major depressive disorder, and then combined with clinical variables using a cross-validated machine-learning regression approach. Unimodal, multimodal and genetically stratified models were trained and validated using ridge, elastic net and random forest regression on 692 patients with bipolar disorder from ten study sites using leave-site-out cross-validation. All models were then tested on an independent test set of 342 patients. The best performing models were then tested in a classification framework.
The best performing linear model explained 5.1% (P = 0.0001) of variance in lithium response and was composed of clinical variables, PRS variables and interaction terms between them. The best performing non-linear model used only clinical variables and explained 8.1% (P = 0.0001) of variance in lithium response. A priori genomic stratification improved non-linear model performance to 13.7% (P = 0.0001) and improved the binary classification of lithium response. This model stratified patients based on their meta-polygenic loadings for major depressive disorder and schizophrenia and was then trained using clinical data.
Using PRS to first stratify patients genetically and then train machine-learning models with clinical predictors led to large improvements in lithium response prediction. When used with other PRS and biological markers in the future this approach may help inform which patients are most likely to respond to lithium treatment.
Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools.
To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.
Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts.
Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.
AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.
Antidepressant medication and interpersonal psychotherapy (IPT) are both recommended interventions in depression treatment guidelines based on literature reviews and meta-analyses. However, ‘conventional’ meta-analyses comparing their efficacy are limited by their reliance on reported study-level information and a narrow focus on depression outcome measures assessed at treatment completion. Individual participant data (IPD) meta-analysis, considered the gold standard in evidence synthesis, can improve the quality of the analyses when compared with conventional meta-analysis.
We describe the protocol for a systematic review and IPD meta-analysis comparing the efficacy of antidepressants and IPT for adult acute-phase depression across a range of outcome measures, including depressive symptom severity as well as functioning and well-being, at both post-treatment and follow-up (PROSPERO: CRD42020219891).
We will conduct a systematic literature search in PubMed, PsycINFO, Embase and the Cochrane Library to identify randomised clinical trials comparing antidepressants and IPT in the acute-phase treatment of adults with depression. We will invite the authors of these studies to share the participant-level data of their trials. One-stage IPD meta-analyses will be conducted using mixed-effects models to assess treatment effects at post-treatment and follow-up for all outcome measures that are assessed in at least two studies.
This will be the first IPD meta-analysis examining antidepressants versus IPT efficacy. This study has the potential to enhance our knowledge of depression treatment by comparing the short- and long-term effects of two widely used interventions across a range of outcome measures using state-of-the-art statistical techniques.
This chapter contains discussion of two distinct skeptical ways around the Darwinian problem of evil. One way is neo-Cartesian theory, according to which we are in no epistemic position to know that animals suffer in a subjective manner comparable to the conscious suffering of human beings. The other is Skeptical Theism, according to which we are in no epistemic position to say with confidence that some apparently gratuitous evils really are gratuitous, i.e., not grounded in morally sufficient reasons that God has for allowing them. The author explains why he does not accept either of these skeptical means of escape from the Darwinian Problem. The prima facie appearance of animal suffering is too strong to be overridden by the reasons and evidence that advocates of the neo-Cartesian view give for such skepticism. Further, the author contends that the absence of God-justifying explanation, which advocates of Skeptical Theism see as expected on theism, is in fact incompatible with the parental goodness of God.
The chapter includes a comprehensive account of the Darwinian problem of evil, centered on evolutionary animal suffering inscribed by natural selection into the conditions of existence. The author contends that the problem arises from the unveiling of a Darwinian World by modern scientists. They have unveiled four interconnected truths about the natural realm, as it has been in the past, and as it is now. The unveilings are (1) “deep evolutionary time,” (2) a “plurality of worlds” existing successively in the planetary past, (3) “aniti-cosmic micro-monsters” that cause widespread, brutal suffering for animals, and (4) “evil inscribed,” i.e., that animal suffering in nature is not accidental, but is systemic – inscribed by natural selection into the conditions of existence for animals. It seems that the source of evolutionary evils suffered by animals is not a Fall, as traditionally alleged by theists, but the design of nature itself.
In this chapter the author considers Aesthetic Theodicy, according to which selected forms of cosmic beauty are valuable enough to justify natural evils suffered by animals. He begins by defending the use of aesthetic values in theodicy on the ground that aesthetic goods often have moral value. He then examines the classical versions of Aesthetic Theodicy, in which one appeals to cosmic harmony, balance, and overall fittingness of all parts into a beautiful and morally valuable whole. This approach fails to account well enough for the extreme disharmony, imbalance, and dysteleology in the Darwinian World, as unveiled by science. Next, he examines post-classical versions, in which one appeals to “major beauty” (so Whitehead) created by cosmic conflict and disintegrative elements of nature. He examines the specific appeal to the tragic moral beauty of evolution, particularly in predation. He argues that these approaches identify morally valuable forms of beauty, but they do not contain scenarios in which God defeats tragic evils for the victims. Nor can the appeal to tragedy account for the existence of Darwinian horrors. He concludes that perhaps sacred canonical sources can help.
This chapter includes a defense of Rolston’s thesis that Darwinian evolution is “cruciform” or “kenotic” in character, i.e., that the self-sacrificial role of animals in nature is strongly analogous to the part played by Jesus Christ in redeeming the world. With Southgate, the author rejects Rolston’s conclusion, however, that the moral goodness of this “cruciformity” outweighs and justifies evolutionary suffering. The Darwinian kenōsis (the author’s phrase) has partial God-justifying force, but for full justification an eschatological sequel is required. The comparison strengthens the position of theism in the controversy on both the evidential and justificatory levels of the Darwinian problem of animal suffering. The author also argues that Paul’s famous digression on divine election in Romans 8-11 provides unexpected help on all these levels. It supports the aesthetic analogue of God as Artist, and the imagery helps to sharpen the thesis taken from Job: God is creating the messianic Cosmos by extraordinary artistic-moral means. In the emergence of the Church from the cross, we can already begin to “see” the truth of this proclamation.
In this chapter, the author explores the book of Job for a perspective on the modern Darwinian Problem of evil. He concurs with recent scholars who reject the commonplace reading of Job, i.e., that God refuses to answer Job’s question: how can his suffering be just? He concurs with Carol Newsom that in the divine speeches at the end, God answers Job indirectly in the form of carefully crafted symbolic poetics, the rhetorical structure and imagery of which radically reconstruct Deuteronomic tradition on God and suffering. The author proposes that the treatment of God and wild animals in Job makes the Darwinian configuration of animal suffering more plausible on canonical theism than commonly supposed. He further proposes that Job provides grounds for belief that the Jewish/Christian God will defeat evils for animals and include them in the messianic eschatological realm. Job offers a religiously framed aesthetic perspective on Darwinian evil that helps us to recover the “theistic sight” in nature that Darwinian discoveries have obscured.
In this chapter, the author offers grounds for belief that, in the eschatological end, God will resurrect, transform, and include all non-human creatures and things in the messianic kingdom of God. Besides philosophical-theological and moral grounds, he appeals to doctrines of the “image of God,” the atonement, and the resurrection in support of this eschatological proposition. Next, he discusses recently offered scenarios of animals in Heaven. He focuses on the identity-problem of predation: will predators transformed into non-predators still be themselves? Finally, he offers his own scenario of God defeating Darwinian evil for animals by elevating them to a stature analogous to the exalted place of martyrs according to Christian tradition.
This chapter comprises dicussion of both informal and formal arguments against belief in the God of theism. Informal arguments rely on an “anyone-can-see” atheistic intuition about nature, unveiled in Darwinian terms. Formal arguments rely on an atheistic inference made from evidence – from the configuration of evolutionary evils suffered by animals in the natural realm, past and present. A successful God-justifying account will have to weaken the atheistic force of these arguments, if not mitigate them altogether. The author proposes that the prospects for success are poor, so long as we approach the problem of God and evolutionary animal suffering on conventional ethical norms for the moral agency of God in creating species. He looks ahead to proposing that aesthetics will play a major role in his own approach to both the teleological and moral aspects of the Darwinian Problem.
This chapter is focused on which moral and epistemic conditions a God-justifying account of evil must meet in order to succeed. The author proposes that such accounts are likely to fail so long as they seek to show that in allowing evil, God has met the Necessity Condition. It requires that to be justified, the evil must be necessary in an absolute sense, i.e., unavoidable, even for God. The author proposes that theists should adopt Roderick Chisholm’s Defeat Condition, instead. It requires that the moral agent “defeat” any evil that s/he allows by integrating it into a valuable whole that both outweighs the evil and could not be as valuable as it is without the evil. In addition, he takes Chisholm’s suggestion that divine moral agency may be better pictured on an aesthetic analogy of God as Artist than on a narrowly ethical one. Further, he adopts Michael Murray’s proposal that a God-justifying account should be at least as plausible as not. In other words, it should be a “case for God” (or causa Dei), in Leibniz’s terms, rather than either a mere logical defense or fully blown theodicy.
In this chapter, the author considers Lapsarian Theodicy, according to which the originating cause of natural evil, including the suffering of animals in nature, was a cosmic Fall set in motion when the first human disobeyed God. He argues that, besides being antiquated by Darwinian science, this traditional explanation of animal suffering fails on four analytical-theological grounds. For it entails (1) an implausible original fragility of the created world, (2) extreme moral impropriety on God’s part, (3) an implausible account of motivation to do evil in paradisiacal circumstances, and (4) an overvaluing of human freedom. Furthermore, the author argues that Lapsarian Theodicy is not supported unambiguously by the story of Adam and Eve in Eden, as commonly assumed. He concludes that theists are best advised to search for non-lapsarian alternatives, as the majority of participants in the controversy are doing.