Psychology and Neuroscience of Affective Disorders Lecture Transcript PDF

Module: Psychology and Neuroscience of Affective Disorders Week 1: Introduction to affective disorders Topic 3: Emerging focuses in affective disorders (Part 3 of 4) Lecture transcript Dr Rebecca Strawbridge Department: Centre for Affective Disorders Slide 4 The last part ended on not the most opti...

Module: Psychology and Neuroscience of Affective Disorders Week 1: Introduction to affective disorders Topic 3: Emerging focuses in affective disorders (Part 3 of 4) Lecture transcript Dr Rebecca Strawbridge Department: Centre for Affective Disorders Slide 4 The last part ended on not the most optimistic note, so let's progress now to developments in terms of new treatments for mood disorders. Slide 5 The first to discuss is ketamine. Ketamine is a dissociative anaesthetic which acts as an antagonist on NMDA receptors. This was the most recent medication to be licensed in the UK for depression and is the first to be licensed with a new therapeutic mechanism of action. Its main benefits over most other antidepressants are its rapid onset of therapeutic effect and its effectiveness for suicidality. Slide 6 There are various ways that ketamine can be administered at lower doses than for other applications, but we see very high effect sizes for reducing depressive symptoms in both bipolar and unipolar depression. Furthermore the antidepressant effect is incredibly rapid, © King’s College London 1 and a single dose can keep symptoms reduced for as long as two weeks. Unfortunately though, the signal then drops off. There is a challenge around how to maintain this for longer especially given concerns about the potential for abuse and dependence, the possible adverse health effects of long-term use, and here I note that we found poor reporting of adverse effects in the trials published to date. The other problem in the evidence base is adequate control arms because there isn't a good placebo, so participants tend to know if they have had ketamine rather than whatever else they might have been randomised to receive. Finally, there are few long-term studies at the moment, so these are the challenges that are now starting to be addressed. Slide 7 There is now a lot of excitement about the potential for psychedelic compounds to be used for treating at least unipolar depression. These represent another rapid-acting intervention with a different mechanism. Psychedelics are defined as hallucinogenic compounds which alter consciousness states across psychological, visual, and auditory domains. Slide 8 Most focus here is on psilocybin with anecdotal evidence of mood-lifting effects dating back centuries. However, this has only recently been possible to examine in controlled clinical trials. So far there is a phase I trial indicating broad safety and tolerability in healthy people, and a randomised controlled trial for people with major depressive disorder suggesting antidepressant efficacy. And there are now several ongoing trials in people with unipolar mood illnesses. Other psychedelics are beginning to be looked at as well, most notably ayahuasca and N-dimethyltryptamine or DMT which have only been subject to uncontrolled studies, and now there is one controlled Phase I trial ongoing in healthy people. Slide 9 Overall, psychedelics could be beneficial over ketamine in a few ways, although here really I'm talking about psilocybin due to lack of evidence of the others. Firstly, the rapid-acting antidepressant effect may last for longer than two weeks. Secondly, there are less concerns over-dependence and long-term adverse effects, but we are much earlier in the research pathway. So there is more uncertainty particularly for people with bipolar disorders. The challenges around blinding and the long-term effects are really the same as for ketamine, and there may be an issue with self-selecting samples. So anecdotally many people in trials have previously sought and felt that they have benefited from these agents, whereas people who did not benefit or concerned to try them for the first time are probably less likely to volunteer for trials. It may also be costly as it's currently thought that psychotherapeutic integration is needed during and after a psychedelic experience to help people benefit affectively. Slide 10 Moving away somewhat from medications now and towards neuromodulation. Neuromodulatory interventions stimulate the brain in one way or another, aiming to change activity and resultantly improve symptoms. Repetitive transcranial magnetic stimulation or TMS is the best evidenced and is considered safe being licensed for depression in the UK. TMS 2 © King’s College London delivers electromagnetic pulses to specific brain regions inducing an electrical current in brain tissues. Some of the benefits of this include there being no adverse long-term effects known about, and it's easy and acceptable to patients. For example, in not requiring anaesthesia. However, the response rates are perhaps not outstanding, lying just under half of patients with as few as one quarter fully remitting from depression. There are also issues aroun d the longevity of antidepressant effects, and there are issues with blinding in these trials as well. Slide 11 Transcranial direct current stimulation or TDCS is another. This involves a low amplitude electrical current applied directly through electrodes placed on the head, targeting brain activity near to the surface. The UK guidelines for depression contain some guidance about TDCS as well, but this is limited. The others listed here; DBS and VNS, that is, deep brain stimulation and vagus nerve stimulation are not provided in the UK. Slide 12 More work is being done around these. The evidence so far is synthesised nicely and clearly in this recent meta-analysis by Mutz et al. This is especially nice as it also includes electroconvulsive therapy which is a source of great controversy as it has a lot of negative connotations and does have to be administered carefully, but it's also considered one of the most effective therapies ever used in this discipline with response rates in people with mood disorders up to 80%. You may wish to pause the video here to take a look at the paper's visual abstract. Slide 13 The last part of this section is focused on treating symptoms or features other than those considered to be core to mood disorders. Anti-inflammatory medications are being trialled to treat mood symptoms, but are included here as focusing on ameliorating different biological abnormalities associated with these illnesses. They have also been observed to improve depressed mood in groups of people with inflammatory illnesses. These treatments have previously been shown to help treat both depression and mania which is relatively rare as most treatments for bipolar disorders have stronger effects on one pole than the other. However, the larger new trials haven't shown particular benefits with anti-inflammatory medications at least to depression. Cognitive and functional enhancement interventions are being particularly heralded for people with cognitive impairment and bipolar disorders. Some of these are psychosocial, for example cognitive remediation therapy or functional remediation therapy. And some are pharmacological including modafinil and lurasidone, and you'll hear more about these in a few weeks. Slide 14 Interpersonal and social rhythm therapy or IPSRT is another psychological approach. This is focused on stabilising circadian rhythms again for overall affective benefits. This is mainly for people with bipolar disorders for whom there appears a stronger circadian element to the illness which is linked with both depressive and manic relapses. So this therapy attempts to target particular elements not considered central to the illness, so circadian routine and also 3 © King’s College London interpersonal difficulties with the aim of preventing recurrence of acute mood epis odes. Finally listed here is suicide-focused interventions which are mainly from therapies already used in people with affective disorders. These include: lithium electroconvulsive therapy, ketamine and dialectical behavioural therapy. So both medication and psychosocial intervention. However, this focus on suicide is a good example of a translational focus of the RDoC approach that we talked about earlier in the heterogeneity section towards thinking about people experiencing a particular difficulty and treating based on that rather than treating people based simply on the diagnosis that they have. Slide 15 This brings us to the end of the treatment development section, and now we're going to move on to the last part of the lecture which focuses on improving treatment but in different ways. 4 © King’s College London