Psychiatric Soma and Palliative Psychopharmacology The use of psychiatric medications to optimise the subjective quality of life of patients with severe treatment-refractory mental health conditions remains a debated topic. We see it's need in severe and enduring conditions where clinically significant 'recovery' may not be the feasible goal, rather making people "feel better" and optimising Quality of Life may be better goals. Arguably, most psychiatry is already palliation of symptoms as these options generally don't actually "cure", they live up to easing the severity of a disease without removing the cause, or effecting a cure. To palliate comes from the Latin 'palliare', to cloak [1]. We also see that there is a significant level of treatment resistance and in severe mental illness, perhaps 20% achieve a 'good response' with conventional pharmacotherapy. Still one would argue increasing quality of life is an important goal of psychiatry at any stage. While curative and rehabilitative psychiatry and (personal) recovery is considered the main approach to mental health, considering the limitedness of curative psychiatry in alleviating suffering in some severe mental illnesses, a palliative approach centred on reducing harm and alleviating suffering directly is needed [2, 3, 4]. - pursuing curative pharmacotherapy of some mental illnesses, such as severe persistent schizophrenia, depression, or anorexia nervosa, might do more harm than good - 20% to 50% of patients with schizophrenia may experience treatment resistance - exposure to further antipsychotics might be intolerable or worsen symptom domains - In major depression, rates of remission after successive medication trials decrease 1 exponentially, often resulting in polypharmacy Where treatments focusing on symptom reduction have failed, one may propose ‘a shift away from focusing on the disorder and towards increasing quality of life, reducing distress and increasing hope for the future’ "Rather than cycling through more interventions with marginal utility, responding with care to the needs of these patients requires prioritizing symptom management and quality of life, reducing harm from aggressive interventions, and minimizing use of physical and chemical force" One fears that using the 'palliative' term however removes hope of positive change and resilience in living with symptoms, instead promoting a nihilistic mentality in patients. Could one be driven away from attempting a better life, and driven towards a hedonistic death drive by endorsement of such thinking? I learnt there can clinically be a switch towards anxiolysis and pain relief in more treatment refractory conditions but also non-pharmacological measures play a significant role, such as shifting mindset and self-expectations and focusing on the little things that bring enjoyment to one's life despite limitations eg one's favourite foods. Initial efforts in a rational framework should be recovery-orientated where the emphasis is on restoring greater well-being and healing and that requires a boost hopefulness to instil such a mindset in patients that people can get better. That said, as suffering becomes more chronic and debilitating, the focus of treatment should arguably shift to realistic aims centred on improved Quality of Life and 'feeling better'. Where medications have not significantly helped, often a shift towards more psychosocial interventions is considered. We see in significant impairments, improving quality of life in cognitive impairment is often mentioned as the most important goal, where factors include improving mood, engagement in pleasant activities, physical functioning, and enhancing cognitive functioning with a focus on simple activities such as 'joy', 'movement', 'hobbies and activities', 'social interactions', 'feeling loved', 'comfort and pain management', 'basic needs' and 'pleasant activities' were all deemed as important for quality of life [5] Other writers such as Brendon Burchard have considered what makes life 'rich and full'. Things like Aliveness. To feel alive, energised, awake, enthusiastic, healthy, vibrant, passionate, Connection. Real relationships. Love. Friendship. Belonging. Meaningful Pursuits. Doing things that matter to us and make us engaged and fulfilled. Arguably, if one was to seek improving Quality of Life pharmacologically, these sorts of domains would be beneficially impacted. The prosocial dimension is not commonly addressed in conventional pharmacotherapy but hopefully the psychopharmacology of the 2 the future will be more prosocial. Short of an empathogenic elixir or some psychostimulants , what sort of medications would offer such personal life enrichment? Fearing creating "Dr Feelgood", or out of fear of sparking addiction/dependence, there is a lot of hesitation to introduce such a palliative psychopharmacology [6] but as with palliative care, we see there is significant suffering and reduced quality of life in the neglect of these dimensions of human suffering. In a cancer patient, use of pain relief and stimulant medications [7] overcame the cognitive burdens and somnolence along with pain allowing them to " maintain cheerful communication with family members.". These sorts of effects namely reductions in pain, depression, somnolence and improvements in cognition have been noted and to me, this highlights simple measures effectively bolstering quality of life. Other medications in palliative care commonly include cannabinoids, analgesics, serotonergic antidepressants, sedative hypnotics, stimulants, and neuroleptics but we also have to consider over-sedation as something that would worsen quality of life, if someone is sent into a somnolent daze and unable to engage with life. At one level, in the overly hedonistic framework, on could see the palliative psychopharmacology being centred at inducing a blanket euphoria over the disease state, or effluxing some nucleus accumbens dopamine. This however, is over-reductionist if one is seeking to enhance Quality of Life. If we were to consider a 'feel good' hedonistic perspective, efforts to activate opioidergic receptors may induce a transient euphoria but the dependence and tolerance issues are too great for longer-term use. Cannabinoids could induce some pain reduction, mood enhancement and anxiolysis. Perhaps more fittingly, efforts to block kappa opioid receptors [8] - currently a focus of research - may offer more promising treatments for the longer- term treatment. Similarly, efforts to enhance dopaminergic activity have significant downfalls where side- effects such as disinhibition and poor decision-making with high risk behaviour, if not induced psychosis can become apparent which could be particularly detrimental with the impaired frontal functions commonly seen. That said, from some studies, low-dose psychostimulants preferentially boost PFC functioning and that enhancement of mesocortical dopamine pathways, whilst attenuating subcortical D2 signalling with combined antipsychotics functions to improve quality of life in some patients with schizophrenia [9] To glimpse into how quality of life can be bolstered, it is perhaps worthwhile looking into terminal illness to consider what gives those suffering some quality of life? A pertinent example is the entheogenic research in the dying [10], where psychological factors such as depression, existential distress, and well-being are addressed. In such studies drastic improvements of mood, life satisfaction, relationships, and meaning, which persisted for more than a year, were mediated by the degree of associated mystical experience. 3 In general patients expressed wanting "to be relatively free from pain, be surrounded by loved ones, and to feel a degree of meaning and well-being". If we assume these fundamentals extend to mental illnesses, can these be pharmacologically manipulated beneficially? We see several factors such as: - freedom from both pain and anxiety - relational enhancements provided which could open an important window for interpersonal connection with family and friends, leading to ' meaningful moments with loved ones'. It was able to address a need where people want to engage in meaningful discussions with loved ones and feel a sense of meaning, but many people experience psychological suffering that prevents such interpersonal connection - re-conceptualising well-being and a healthy cognitive mindset regarding one’s own death in a way that could be considered broadly “spiritual” There is also mention by Charlton and McKenzie (2004) that psychiatry serves a public health goal of protecting society from 'mad people' and in doing so, the optimisation of a patient's quality of life becomes a far lesser concern than public safety. On that point, we have to consider how much societal suffering could be reduced if people suffering debilitating mental health conditions "felt good"? Could we inspire, rather than patients involved in self-harm or violence, a 'crazy dance' or hug-fest if we optimised the pharmacopeia towards actually effective 'happy drugs' [11]? [1] Singh AR. Modern Medicine: Towards Prevention, Cure, Well-being and Longevity. Mens Sana Monogr. 2010 Jan;8(1):17-29. https://doi.org/10.4103/0973-1229.58817 [2] Michelle Raji, Palliative Approaches to Psychiatry AMA J Ethics. 2023;25(9):E653-654. doi: 10.1001/amajethics.2023.653. https://journalofethics.ama-assn.org/article/palliative- approaches-psychiatry/2023-09 [3] Strand, M., Sjöstrand, M. & Lindblad, A. A palliative care approach in psychiatry: clinical implications. BMC Med Ethics 21, 29 (2020). https://doi.org/10.1186/s12910-020-00472-8 [4] Trachsel, Manuel et al. Palliative psychiatry for severe and persistent mental illness The Lancet Psychiatry, Volume 3, Issue 3, 200 https://doi.org/10.1016/S2215-0366(16)00005-5 [5] Logsdon RG, McCurry SM, Teri L. Evidence-Based Interventions to Improve Quality of Life for Individuals with Dementia. Alzheimers care today. 2007;8(4):309-318. [6] Charlton BG, McKenzie K. Treating unhappiness – society needs palliative psychopharmacology. British Journal of Psychiatry. 2004;185(3):194-195. 4 https://doi.org/10.1192/bjp.185.3.194 [7] Rozans, M., Dreisbach, A., Lertora, J. J. L., & Kahn, M. J. (2002). Palliative Uses of Methylphenidate in Patients With Cancer: A Review. Journal of Clinical Oncology, 20(1), 335–339. https://doi.org/10.1016/10.1200/jco.2002.20.1.335 [8] Demyttenaere K. Aticaprant, a kappa opioid receptor antagonist, and the recovered 'interest and pleasure' in the concept of major depressive disorder. Eur Arch Psychiatry Clin Neurosci. 2024 Jul 6. https://doi.org/10.1016/10.1007/s00406-024-01851-7 [9] Swerdlow NR, Bhakta SG, Talledo J, Benster L, Kotz J, Lavadia M, Light GA. Lessons learned by giving amphetamine to antipsychotic-medicated schizophrenia patients. Neuropsychopharmacology. 2019 Dec;44(13):2277-2284. https://doi.org/10.1016/10.1038/s41386-019-0495-4 [10] Yaden, D. B., Nayak, S. M., Gukasyan, N., Anderson, B. T., & Griffiths, R. R. (2021). The potential of psychedelics for end of life and palliative care. Disruptive psychopharmacology, 169-184. [11] B.G. Charlton, Palliative psychopharmacology: a putative speciality to optimize the subjective quality of life, QJM: An International Journal of Medicine, Volume 96, Issue 5, May 2003, Pages 375–378, https://doi.org/10.1093/qjmed/hcg055 5