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<channel><title><![CDATA[Professor Paul B Fitzgerald - Blog]]></title><link><![CDATA[https://www.paulbfitzgerald.com/blog]]></link><description><![CDATA[Blog]]></description><pubDate>Thu, 22 Jan 2026 19:25:26 +1100</pubDate><generator>Weebly</generator><item><title><![CDATA[Mental Health consequences of lockdown are absolutely no reason to limit COVID related restrictions.]]></title><link><![CDATA[https://www.paulbfitzgerald.com/blog/mental-health-consequences-of-lockdown-are-absolutely-no-reason-to-limit-covid-related-restrictions]]></link><comments><![CDATA[https://www.paulbfitzgerald.com/blog/mental-health-consequences-of-lockdown-are-absolutely-no-reason-to-limit-covid-related-restrictions#comments]]></comments><pubDate>Fri, 14 Aug 2020 10:20:13 GMT</pubDate><category><![CDATA[Uncategorized]]></category><guid isPermaLink="false">https://www.paulbfitzgerald.com/blog/mental-health-consequences-of-lockdown-are-absolutely-no-reason-to-limit-covid-related-restrictions</guid><description><![CDATA[       I have been wanting to write something for a few weeks in response to what I keep seeing as spurious arguments against the escalation of COVID restrictions in Victoria, and around the world, which use &ldquo;mental health&rdquo; as a reason to suggest we should not be increasing social restrictions.As I understand it, the argument goes that the mental health consequences of the damage to the economy, job losses, unemployment and social dislocation resulting from enforced economic and soci [...] ]]></description><content:encoded><![CDATA[<div><div class="wsite-image wsite-image-border-none " style="padding-top:10px;padding-bottom:10px;margin-left:0;margin-right:0;text-align:right"> <a> <img src="https://www.paulbfitzgerald.com/uploads/1/2/6/0/126089503/published/engin-akyurt-0ccfnk0-rzg-unsplash.jpg?1597400515" alt="Picture" style="width:931;max-width:100%" /> </a> <div style="display:block;font-size:90%"></div> </div></div>  <div class="paragraph">I have been wanting to write something for a few weeks in response to what I keep seeing as spurious arguments against the escalation of COVID restrictions in Victoria, and around the world, which use &ldquo;mental health&rdquo; as a reason to suggest we should not be increasing social restrictions.<br /><span></span>As I understand it, the argument goes that the mental health consequences of the damage to the economy, job losses, unemployment and social dislocation resulting from enforced economic and social lockdown will exceed the impact of COVID infections themselves. Suicide rates will rise and the resultant loss of life may exceed that associated with COVID related deaths, or at least mitigate the reductions in death we achieve through tighter restrictions.<br /><span></span>I think this is just a somewhat more complex extension of the binary argument that has been presented now for several months: that we have a simple choice. We shut down the economy to fight the virus with harsh economic consequences (and effects on mental health) or we do the opposite to support the economy at a cost to physical health / higher rates of viral infection and COVID deaths.<br /><span></span>This is a completely false choice.<br /><span></span><br /><br /><span></span></div>  <div>  <!--BLOG_SUMMARY_END--></div>  <div class="paragraph">Let me repeat that as many just don&rsquo;t seem to get it: we do not have a choice. The economy, and peoples mental health, is going to be dramatically effected whatever we do.<br /><span></span>As we are shutting down the economy, restricting economic and social activity this is having important and damaging mental health consequences. Every day I am seeing patients whose mental health has dramatically worsened during the pandemic and social isolation and unemployment are playing a significant role in driving these problems.<br /><span></span>However, it will be no different if we don&rsquo;t impose the lockdown measures required to get COVID under control. A society with more shops open and more businesses operating is not one that is going to result in better mental health outcomes.<br /><span></span>First, this will not necessarily support better economic outcomes. The reduction in GDP in Sweden has been similar to that in other Nordic countries, at a much greater loss of life<a href="https://medium.com/@pbfitzgerald/mental-health-consequences-of-lockdown-are-absolutely-no-reason-to-limit-covid-related-restrictions-b4b7b1cea0c7#_ftn1">[1]</a>.<br /><span></span>Second, more widespread COVID infections will directly worsen mental health outcomes. COVID infection leaves lasting mental health consequences<a href="https://medium.com/@pbfitzgerald/mental-health-consequences-of-lockdown-are-absolutely-no-reason-to-limit-covid-related-restrictions-b4b7b1cea0c7#_ftn2">[2]</a>. These can arise directly from viral brain infection or the trauma of the illness experience itself, let alone the impact of chronic post viral physical illnesses that seems to characterise this disease. This is before we even consider the effects of grief as many would lose cherished love ones and the impact of the fear in the community that widespread viral spread will have.<br /><span></span>Finally, what about the mental, as well as physical health, of healthcare workers. Hospitals around Melbourne (and in many places in the world) have growing numbers of infected workers, and many sidelined due to possible exposure. The job of caring for the community, people presenting with COVID as well as with strokes and heart attacks, is falling on the shoulders of a shrinking workforce, who also have families at home worried their family member will fall ill, or bring COVID home.<br /><br />Increased rates of infection resulting from relaxing restrictions will have direct impacts on the mental health of individuals, their families and marked adverse consequences for health care workers. And the status quo is also unacceptable. The current rate of daily new cases in Melbourne (400- 700 per day), pales by comparison to some places in the world but is not sustainable for the health system or society in general.<br /><span></span>For these reasons we have &ldquo;simply no choice&rdquo;. We have to act aggressively and with the cooperation of everyone in the community. The government has no choice but to impose strict sanctions on all of us, especially constraining the behaviour of those who cannot see the impact of their actions on others.<br /><br />Regardless of what we do we are going to end up with a major hit to the economy and significant widespread mental health issues. However, one option leads us to also have an overwhelmed healthcare system, deaths and illnesses in healthcare workers and higher rates of physical and mental health illnesses directly related to COVID infection. I don&rsquo;t want to be part of a society that chooses this option in the misguided belief that it is the pathway to sustain corporate profits and the share market. Or in the mistaken, but perhaps more well intentioned belief, that it is the way to support mental health.<br /><span></span>To support mental health we need generous financial supports to mitigate income loss, extensions of health care programs to ensure all members of society have timely and affordable access to mental health support and a united society dedicated to finding all the innovative ways we can to support one another. We would be much better off channelling our energy in these directions than in these debates.<br /><span></span><a href="https://medium.com/@pbfitzgerald/mental-health-consequences-of-lockdown-are-absolutely-no-reason-to-limit-covid-related-restrictions-b4b7b1cea0c7#_ftnref1">[1]</a>&nbsp;<a href="https://www.nytimes.com/2020/07/07/business/sweden-economy-coronavirus.html" target="_blank">https://www.nytimes.com/2020/07/07/business/sweden-economy-coronavirus.html</a><br /><span></span><a href="https://medium.com/@pbfitzgerald/mental-health-consequences-of-lockdown-are-absolutely-no-reason-to-limit-covid-related-restrictions-b4b7b1cea0c7#_ftnref2">[2]</a>&nbsp;<a href="https://www.sciencedirect.com/science/article/pii/S0889159120316068" target="_blank">https://www.sciencedirect.com/science/article/pii/S0889159120316068</a><br /><span></span></div>]]></content:encoded></item><item><title><![CDATA[Why developing a vaccine may just well be the easiest step.]]></title><link><![CDATA[https://www.paulbfitzgerald.com/blog/why-developing-a-vaccine-may-just-well-be-the-easiest-step]]></link><comments><![CDATA[https://www.paulbfitzgerald.com/blog/why-developing-a-vaccine-may-just-well-be-the-easiest-step#comments]]></comments><pubDate>Fri, 14 Aug 2020 10:16:21 GMT</pubDate><category><![CDATA[Uncategorized]]></category><guid isPermaLink="false">https://www.paulbfitzgerald.com/blog/why-developing-a-vaccine-may-just-well-be-the-easiest-step</guid><description><![CDATA[       The Prime Minister gathered all his expert advisors around him. He had just been told that finally a vaccine was available for the terrible disease that afflicted the country. But there were not enough doses for everyone: what was he to do?&ldquo;Vaccinate the doctors first, we have to treat all the patients&rdquo; said his chief medical officer.&ldquo;Vaccinate all the epidemiologists first, you need us to understand the disease&rdquo; said his top public health officer.&ldquo;Vaccinate  [...] ]]></description><content:encoded><![CDATA[<div><div class="wsite-image wsite-image-border-none " style="padding-top:10px;padding-bottom:10px;margin-left:0;margin-right:0;text-align:center"> <a> <img src="https://www.paulbfitzgerald.com/uploads/1/2/6/0/126089503/virus-4030721-1920_orig.jpg" alt="Picture" style="width:auto;max-width:100%" /> </a> <div style="display:block;font-size:90%"></div> </div></div>  <div class="paragraph"><em><font size="3">The Prime Minister gathered all his expert advisors around him. He had just been told that finally a vaccine was available for the terrible disease that afflicted the country. But there were not enough doses for everyone: what was he to do?</font></em><br /><em><font size="3">&ldquo;Vaccinate the doctors first, we have to treat all the patients&rdquo; said his chief medical officer.</font></em><br /><em><font size="3">&ldquo;Vaccinate all the epidemiologists first, you need us to understand the disease&rdquo; said his top public health officer.</font></em><br /><em><font size="3">&ldquo;Vaccinate all the economists first, without us you won&rsquo;t be able to understand the financial problems this disease is causing&rdquo; said the head of the Treasury.</font></em><br /><em><font size="3">&ldquo;What about the factory workers&rdquo;: said the Industry head, &ldquo;without them we wont be able to make anything&rdquo;.</font></em><br /><em><font size="3">&ldquo;STOP&rdquo; shouted the PM, exasperated and at his wits end. What do you think he said to the junior aid who was trying to avoid his gaze. &ldquo;What would you do?&rdquo;</font></em><br /><em><font size="3">&ldquo;I&hellip;I..&rdquo; stammered the aid. &ldquo;I don&rsquo;t want it, I don&rsquo;t care who you give it too first, I am not a fool &mdash; I have read about these things on the internet &mdash; these vaccines, they do more harm than good&rdquo;.</font></em><br /><em><font size="3">The PM pondered this for a while and then commanded. &ldquo;Find everyone who doesn&rsquo;t want to be vaccinated. Find a way to persuade them to have it: they are the ones we need to have vaccinated first&rdquo;</font></em><br />So I think pretty much everyone sees the development of an effective vaccine as the way we get out of the predicament of the COVID-19 pandemic. Whether you are for locking down for the long term, graded reopening or want to open the economy and damn the health consequences, I think pretty much everyone now accepts we don&rsquo;t get back to a world that resembles anything like the one we all used to know without an effective vaccine. Sure some places, New Zealand being the outstanding example, have effectively eliminated the virus for periods of time. But for how long can countries remain isolated. Like personal isolation this will eventually take its toll: on the economy and on the individual desires and freedoms of the population. This is not a long term future we desire.<br />There is fortunately, a remarkable effort going on around the world to develop an effective and safe vaccine. In fact, given the number of competitive development programs it is quite feasible that we might end up with more than one, and possibly even quite a number of useful vaccines. It is sobering to realise that we haven&rsquo;t ever successfully developed a vaccine in less than 5 years before &mdash; imagine what it would be like living in a COVID prevalent world for half of the next decade &mdash; but the intensity and breadth of the vaccine efforts at the moment gives me optimism that we won&rsquo;t just beat, but will obliterate, this record.<br /><br /><br /></div>  <div>  <!--BLOG_SUMMARY_END--></div>  <div class="paragraph">However, the successful development of a vaccine will not be the end of our problems and will pose a series of issues which as a community we need to start thinking about and discussing now. If we wait until a vaccine is available it will be too late. We will be left making decisions on the run: we all know how well that has turned out in this pandemic so far!<br /><span></span>The first issue relates to how we are going to ensure enough of our population is open to accepting vaccination. Vaccine skepticism, driven by the divisive rantings of often charismatic but misguided individuals on the internet, fringe religious groups and polarising political actors has never seemed to be so prominent. This is especially the case in the US &mdash;&nbsp;<a href="https://www.axios.com/coronavirus-vaccine-poll-age-race-8a9d6384-aa63-4c29-9b33-1c0ad4f4fd9f.html" target="_blank">a recent poll</a>&nbsp;reported that 35% of the population does not plan to be vaccinated but also pervades other countries, including Australia. Campaigns against mask wearing and other public health pronouncements have also acted to undermine trust in public health recommendations. They have fostered an atmosphere where what you believe or accept in regards to health recommendations has become more influenced by your politics than what is the received wisdom of experts.<br /><span></span>This unfortunately, is just one nasty consequence of an increasing mistrust of expert opinion in society in general.<br /><span></span>As American Historian Richard Hofstadter<a href="https://www.goodreads.com/book/show/241061.The_Paranoid_Style_in_American_Politics_and_Other_Essays" target="_blank">&nbsp;stated way back in 1964</a>,<br /><span></span>&ldquo;<em>However, in a populistic culture like ours, which seems to lack a responsible elite with political and moral autonomy, and in which it is possible to exploit the wildest currents of public sentiment for private purposes, it is at least conceivable that a highly organized, vocal, active, and well-financed minority could create a political climate in which the rational pursuit of our well-being and safety would become impossible</em>.&rdquo;<br /><span></span>He has also described&nbsp;<a href="https://www.amazon.com.au/Anti-Intellectualism-American-Life-Hofstadter/dp/0394703170" target="_blank">anti-intellectualism</a>&nbsp;as the view that intellectuals are &ldquo;pretentious, conceited&hellip; and very likely immoral, dangerous and subversive&rdquo;.<br /><span></span>I don&rsquo;t think it is hard to make an argument that things have only worsened since the publication of these works and events during the current pandemic have brought this home with considerable force.<br /><span></span>There is also fairly clear evidence of the link between general anti-intellectual views and opposition to scientific recommendations. Erick Merkley in a recently published&nbsp;<a href="https://academic.oup.com/poq/article-abstract/84/1/24/5758079?redirectedFrom=fulltext" target="_blank">study</a>&nbsp;found a clear relationship between anti-intellectualism and opposition to scientific recommendations on issues such as water fluoridation and climate change. Importantly, this study showed that individuals with anti-intellectual views are likely to hold more firmly their opposition to ideas presented as a result of expert consensus.<br /><span></span>This is a really important finding. We are clearly not going to convince the vaccine skeptical proportion of the population through appeals to expert opinion, no matter how strongly these ideas are supported by scientific evidence. Instead, we need to reconsider how we promote the hopefully soon to come COVID-19 vaccines.<br /><span></span>Given that Merkley also found that anti-intellectualism seems to be connected to populism, perhaps we need to come up with novel ways to promote vaccine adherence turning this finding on its head. Should we promote vaccination through aggressively jingoistic appeals to patriotism? What about if we promote vaccination through advertising where compliance with vaccinations is positively associated with certain class affiliations, even if these groups are more commonly vaccination skeptical?<br /><span></span>I don&rsquo;t know the answer to these questions but they are ones we need to be addressing now. Research to address this will only take a minor fraction of the funding been pumped into vaccine development itself, but if we don&rsquo;t tackle this immediately, vaccine resistance has the capacity to dramatically undermine our capacity to establish true herd immunity. Waiting until we actually have a vaccine will be too late.<br /><span></span>The other conversation we must begin to have now relates to the process of vaccination roll out when it becomes available. Clearly there is going to be a process of escalation of vaccine availability such that systematic decisions are going to have to be made in regards to how we prioritise vaccine delivery.<br /><span></span>It makes rather obvious sense to have some groups at the top of this list. Health care workers, especially those in the front line of helping patients with this illness, clearly need to be protected as soon as possible, really in the interests of everybody. There are a variety of other so-called essential workers for whom it would make sense to prioritise early access to vaccination.<br /><span></span>It is less clear, however, how we roll out vaccination after we address these initial groups. For example, the elderly are clearly the most vulnerable to the most serious health effects of COVID, and a sensible argument could be made to progress with vaccination from the elderly downwards across the age groups.<br /><span></span>A meaningful counterargument can be made, however, that viral spread appears to be driven by younger people and so perhaps we should do the opposite.<br /><span></span>It can also be argued that the younger members of society are actually bearing the greatest long-term burden arising from the pandemic. Compromised education will have a profound generational impact on health, earning potential and quality of life.<br /><span></span>I must admit though, that I find it hard to envision a situation where the interests of the young are prioritised in many western societies. This would be so inconsistent with our recent history where successive generations of leaders, and those who vote for them, have been quite happy to mortgage the future for the profits of coal miners and lucrative real estate price escalation.<br /><span></span>I think that how we address this issue will have impacts not just in the coming years but for decades to follow. We already have young generations priced out of the housing market, with derailed educational and career progression and who will be saddled with the future societal debts we are rapidly accumulating as we battle not just to overcome COVID but prevent complete economic meltdown (and to support the stock and real estate portfolios of predominately the older generations of our societies). Open acknowledgement of these disastrous consequences, and their broader context, would be a sensible component of the discussion and one that should be approached proactively to try and help mitigate intergenerational resentment and conflict.<br /><span></span>The abiding message here is that we need to start thinking about these issues now. We need the type of mature considered conversations that our polarised societies most struggle with. We need to engage people widely: across social, generational, political and ideological lines. We need to understand the&nbsp;<em>whys</em>&nbsp;to get to the&nbsp;<em>hows</em>. In doing this we need to treat people with respect, to understand and engage rather than to judge and pontificate. We are all in this together &mdash; whether we like it or not &mdash; it is up to us all to work out how we are in it and how we can come together lest this be yet another reason to further drive us apart.<br /><span></span></div>]]></content:encoded></item><item><title><![CDATA[What can we learn from the tortuous path to widespread clinical approval of the use of TMS therapy for depression?]]></title><link><![CDATA[https://www.paulbfitzgerald.com/blog/what-can-we-learn-from-the-tortuous-path-to-widespread-clinical-approval-of-the-use-of-tms-therapy-for-depression]]></link><comments><![CDATA[https://www.paulbfitzgerald.com/blog/what-can-we-learn-from-the-tortuous-path-to-widespread-clinical-approval-of-the-use-of-tms-therapy-for-depression#comments]]></comments><pubDate>Mon, 15 Jun 2020 08:40:16 GMT</pubDate><category><![CDATA[Uncategorized]]></category><guid isPermaLink="false">https://www.paulbfitzgerald.com/blog/what-can-we-learn-from-the-tortuous-path-to-widespread-clinical-approval-of-the-use-of-tms-therapy-for-depression</guid><description><![CDATA[    Doing TMS circa 2002   The development of transcranial magnetic stimulation (TMS) as a therapy for patients with a depression, has been one of the most important fundamental advances in psychiatric therapeutics since the 1960&rsquo;s. This is not just hyperbole. Almost all of the drugs we use in psychiatry today are derivative of approaches developed in the 1950s and 1960s. Psychotherapy has certainly improved and evolved but again, the forms used today are direct descendants of approaches d [...] ]]></description><content:encoded><![CDATA[<div><div class="wsite-image wsite-image-border-none " style="padding-top:10px;padding-bottom:10px;margin-left:0px;margin-right:0px;text-align:center"> <a> <img src="https://www.paulbfitzgerald.com/uploads/1/2/6/0/126089503/doing-tms-slide-pic_orig.jpg" alt="Picture" style="width:auto;max-width:100%" /> </a> <div style="display:block;font-size:90%">Doing TMS circa 2002</div> </div></div>  <div class="paragraph"><font size="3">The development of transcranial magnetic stimulation (TMS) as a therapy for patients with a depression, has been one of the most important fundamental advances in psychiatric therapeutics since the 1960&rsquo;s. This is not just hyperbole. Almost all of the drugs we use in psychiatry today are derivative of approaches developed in the 1950s and 1960s. Psychotherapy has certainly improved and evolved but again, the forms used today are direct descendants of approaches developed decades ago. Finally, ECT certainly has improved but remains fundamentally connected to its past. TMS, in contrast, is one of the few essentially new treatments that have developed de novo, and one already helping many thousands of patient.<br /><br />TMS is really not new, but is only making headway as a treatment in many places around the world now, and only slowly. In fact, the time it has taken for TMS to develop as a treatment has really been quite considerable. The first TMS machine was developed in 1985 but we can&rsquo;t really date therapeutic TMS from this time as that device could not provide the repetitive stimulation need for treatment applications. Machines that could, however, were developed within the following decade and the first meaningful trials of TMS in depression were published in 1995. It took 13 years until a TMS machine was first approved by the FDA in the US but it is has taken many more years than this, in the majority of cases well over another decade, for approval and widespread uptake to occur in most other countries. This is still not universal.</font><br /><br /></div>  <div>  <!--BLOG_SUMMARY_END--></div>  <div class="paragraph"><font size="3">So given the clear value of TMS, and the inferred premise that it would be better for uptake to have been more widespread, and much more rapid, what can we learn from this experience? In particular, given the increasing proliferation of other brain stimulation techniques, are there lessons that can inform how we address the development of these?<br /><br />First, it is worth considering the clinical trials that were conducted to evaluate the efficacy of TMS, and those that have been used to test other techniques such as transcranial direct current stimulation (tDCS). In both of these cases, the vast majority of studies have been single site investigator initiated trials with relatively small sample sizes. These type of studies can have value. When a treatment is quite new, smaller studies are appropriate to establish proof of concept. This will be the approach often adopted in phase IIa pharmaceutical trials: get a reasonable indication that there is a therapeutic effect and some indication of the characteristics of the treatment (like an indicative dose range).<br /><br />However, in the pharmaceutical industry, where there are strong incentives to progress drug development as quickly as possible, positive indications in phase II will usually lead quite directly to substantial phase III trials. This direct progression was mimicked far less&nbsp; effectively in the TMS case. Although an industry sponsored trial was conducted in the mid 2000&rsquo;s, and a multi-site NIH sponsored trial followed on from this, this all occurred after the conduct of a really diverse array of small, mostly underpowered trials. These trials ultimately contributed very little to the clinical progression of the treatment.<br /><br />Now clearly the commercial status of TMS played a large role in this story. The conduct of the Neuronetics registration trial in the mid 2000&rsquo;s, and the Brainsway registration trial of deep TMS that followed later, were only possible because these companies had unique intellectual property related to their TMS coils: these provided for the possibility of some temporary market monopoly motivating the considerable investment (tens of millions of dollars) spent to conduct these trials. In contrast, the first companies selling TMS machines did not have the intellectual property protection or financial wherewithal to sponsor major research endeavours.<br /><br />These financial factors have influenced every aspect of the spread and uptake of TMS since that time.&nbsp; Outside the US market, there has been very limited commercial sponsorship of regulatory applications and few attempts by industry to systematically collect additional clinical trial or health economic data that might be needed for regulatory or funding approval in smaller or more fragmented markets.<br /><br />The situation in Australia is a good case in point. Registration of medical devices with the Therapeutics Goods Administration (TGA) to allow clinical use in Australia is relatively uncomplicated using a system harmonized with the EU. Therefore, multiple TMS devices have progressively been listed for clinical use. However, regulatory listing does not link to public funding, and outside the provision of TMS to inpatients in private psychiatric hospitals &ndash; a uniquely Australian and lucrative activity for these hospitals &ndash; widespread adoption of outpatient TMS has not occurred yet in Australia, over 20 years after the first trials were conducted in the country. Funding for outpatient TMS can only come through the public funding agency Medicare (private insurers cannot fund outpatient procedures like TMS). However, there has been no attempt by the TMS device manufacturers to initiate and carry forward a funding application. Neuronetics flirted with the idea of doing this for some time but ultimately chose not to and the lack of monopoly status, and the relatively small scale of the other manufacturers presumably prevented them from taking on this task.<br /><br />It was ultimately left to a series of individual psychiatrists to attempt this, under the distant and uninvolved mandate of the Royal Australian and New Zealand College of Psychiatrists. It is worthy of note that the college refused to provide any practical financial or professional support to these applications, the last of which has passed the committee review considered the most critical step to achieve funding. A number of applications were filed over time: I was responsible for the last three in a process spanning seven years.<br />From this experience I can confidently say the delay in achieving approval was directly related to the lack of professional, experienced support. This is not a job to be taken on by busy clinicians or researchers with any expectation of success. As an aside, our success only really became possible when I persuaded a group of TMS device manufactures and distributors to contribute relatively limited amounts each to help pay for the services of a professional agency to help in the process of preparation of our applications. Without this, I do not think we would have had any chance of success. In contrast, a professionally authored application may well have had success quite some time ago, making TMS therapy accessible to patients years earlier.<br /><br />The stop start process we engaged in, learning a lot but taking a long time, is quite different from that which would be taken by a company of meaningful size applying for regulatory approval of a drug or device. Established companies have experienced regulatory teams with the health economic expertise often required to support these applications and they would not expect a process like this to take seven years, or over a decade.<br /><br />It is also notable that uptake internationally of TMS has been highly varied. In part this has related to the location in certain countries of TMS research expertise: hubs around which clinical programs and training&nbsp; can develop. Early adoption of new therapies often develops out centers of research excellence. However, it is more influenced by the regulatory factors we have been discussing and whether there is the capacity of industry, or clinical groups, to navigate the regulations on a country by country basis.<br />It is also true that the evidence required by regulatory agencies differs significantly between countries. Companies are motivated to conduct traditional sham controlled trials as these are typically required by the FDA in gain access to the lucrative US market. In Australia, however, the Medicare Services Advisory Committee evaluates new therapies based on where a new treatment is proposed to fit into a defined clinical protocol. They are most interested in trials evaluating efficacy compared to the existing standard of care, not sham or placebo treatment. This greatly limits the applicability of data collected for US approval to the Australian assessment process.<br /><br />So what can we learn from this? To more effectively progress the development of new brain stimulation therapies, or other novel treatments, especially those without strong industry support? I think the main thing we can do, when developing and testing new treatment approaches, is to organize and collaborate more.&nbsp; Groups getting together to conduct multi-site trials have much more capacity to progress the field than researchers or groups conducting smaller studies in isolation. Collaboration means compromise. Not everyone will have their &lsquo;special&rsquo; protocol tested: trials need to be developed by consensus. However, doing a small study of your special protocol is probably not going to advance it all that much anyway.<br /><br />Collaborative studies are complex to get funded and to conduct.&nbsp; This is especially challenging if we are reaching across national boundaries. However, grant agencies are increasingly interested in international collaboration (and hopefully this will survive COVID!). Researchers have to accept that being a mid level author on an outstanding paper describing a large successful collaborative trial is as good, if not better than, being first author on a much less prestigious publication. Some areas have done this extremely well. Clinical trials performed by intensive care researchers in Australia are routinely published in the very best journals as they are conducted regularly by a highly functional national clinical trials network. They get great publications, but more importantly, regularly impact clinical practice as they are large and substantive trials. We also need to learn to judge our colleagues track records, when they apply for grants or promotion, to take this into account.<br /><br />I think we can also usefully adopt a more commercially oriented mindset when conducting clinical trials, even when these are investigator initiated and not connected to industry anyway. Is the trial being proposed explicitly a proof of concept study and if concept has been established, should we not progress quite rapidly to something definitive?<br /><br />The approval of &lsquo;theta burst&rsquo; TMS for use in depression by the FDA in the US in recent years has established a really meaningful precedent. This approval came from a clinical trial that was exclusively conducted by independent researchers without any industry involvement. It should inspire the field to think about how studies we conduct can be developed in a way that can be used in regulatory applications as in reality this is the most direct pathway towards widespread clinical use. This might involve thinking about the actual design of specific trials or the collection of data that can support health economic evaluations. It certainly will always involve consideration of the size and scope of the proposed research.<br />&#8203;<br />We should also think about whether we can develop new models of engagement between academic groups and companies in the brain stimulation area. Many brain stimulation device manufacturers are quite small and have either struggled to, or chosen not to, invest the substantial money required to conduct registration scale clinical trials. If promising intellectual property is held by a company that does not have the capacity to conduct the clinical trials to advance a specific application, having these studies done by a publicly funded research group might seem quite unreasonable to some if the commercial benefit of the outcomes of this research are exclusively captured in the future by the company in question. Perhaps there is a way in which future commercial earnings related to this research can somehow be shared with the researchers who have done the critical work to develop the approach or even the agency responsible for funding it. This type of idea would require a fundamental reconsideration of the relationships between government funded research, university or hospital research centers and industry but certainly warrants consideration and thought.<br /><br />In summary, the clinical development of forms of non invasive brain stimulation has so far been inefficient: too slow and fragmented to provide patients with access to new treatments, especially TMS, in a timely manner that reflects the seriousness of their illnesses. &nbsp;Researchers need to think carefully in the design and implementation of new studies: we need to learn from our successes and our failures. We need to be both creative and determined and to be constantly aware of the pressing clinical needs that motivate the development of novel therapeutics for disorders affecting mental health.</font><br /></div>]]></content:encoded></item><item><title><![CDATA[A meta-rant about meta-analysis]]></title><link><![CDATA[https://www.paulbfitzgerald.com/blog/a-meta-rant-about-meta-analysis]]></link><comments><![CDATA[https://www.paulbfitzgerald.com/blog/a-meta-rant-about-meta-analysis#comments]]></comments><pubDate>Wed, 03 Jun 2020 12:31:04 GMT</pubDate><category><![CDATA[Uncategorized]]></category><guid isPermaLink="false">https://www.paulbfitzgerald.com/blog/a-meta-rant-about-meta-analysis</guid><description><![CDATA[       The escalating publication of redundant, unnecessary and misleading meta-analyses is a growing blight which requires containment.As a journal editor and reviewer I am repeatedly receiving, and now frequently recommending rejection for, meta-analyses of studies in the brain stimulation field. For a long time these were studies of transcranial magnetic stimulation (TMS), but now meta-analyses of transcranial direct current stimulation (tDCS) studies are propagating faster than the studies e [...] ]]></description><content:encoded><![CDATA[<div><div class="wsite-image wsite-image-border-none " style="padding-top:10px;padding-bottom:10px;margin-left:0;margin-right:0;text-align:center"> <a> <img src="https://www.paulbfitzgerald.com/uploads/1/2/6/0/126089503/photo-of-person-holding-black-tablet-3740162_orig.jpg" alt="Picture" style="width:auto;max-width:100%" /> </a> <div style="display:block;font-size:90%"></div> </div></div>  <div class="paragraph"><font size="3"><span style="color:rgb(42, 42, 42)">The escalating publication of redundant, unnecessary and misleading meta-analyses is a growing blight which requires containment.</span><br /><span style="color:rgb(42, 42, 42)">As a journal editor and reviewer I am repeatedly receiving, and now frequently recommending rejection for, meta-analyses of studies in the brain stimulation field. For a long time these were studies of transcranial magnetic stimulation (TMS), but now meta-analyses of transcranial direct current stimulation (tDCS) studies are propagating faster than the studies exploring the use of the technique themselves. Why is this a problem, why am I ranting and why should anyone care?</span></font></div>  <div>  <!--BLOG_SUMMARY_END--></div>  <div class="paragraph"><font size="3">First, for readers unfamiliar with the area, what is a meta-analyses? Basically, meta-analysis is a statistical approach that combines the effects seen across multiple clinical trials (or other types of studies). In other words, the results of a number of similar clinical trials are brought together in a single analysis to evaluate whether the body of research has successfully answered a particular question. Meta-analysis can be used to analyze the results of a variety of different types of studies but this approach is especially commonly used to pool the results of clinical trials. For example, if 30 studies have tested whether a specific type of medication is effective in depression, with some studies saying yes and some no, what does the collection of these studies conclude?<br />As they can be used to synthesize the results of evidence in this way, meta-analyses are considered the &lsquo;top&rsquo; level of evidence supporting the effectiveness or otherwise of a new treatment. Some regulatory authorities will require positive meta-analyses prior to approval of a new therapy and even more commonly they are required before a treatment is recommend for use in professional clinical practice guidelines.<br />Meta-analyses are also often very popular with journals: a positive meta-analysis is likely to widely cited by other articles and the number of times an article is cited directly affects the so called impact factor of a journal, often seen as a reflection of the quality and exclusivity of the journal itself.<br />The development of meta-analyses has seen the development of a particular subset of academic: those who don&rsquo;t actually do original research but just conduct and publish these analyses. Building a career like this clearly does not require obtaining large grants to support research teams or the long slog of subject recruitment into clinical trials and studies and can lead to highly cited publications in top ranked journals.<br />So what is the problem with all this? Well, the problem is not with the technique itself but its application. As these methods can be learnt relatively easily, their application has spread rapidly, now frequently to a point where they are addressing questions well beyond those they should, or are addressing them in problematic ways. How?<br />Well first, meta-analyses are being conducted where the underlying body of evidence really just doesn&rsquo;t justify the conduct of the analysis: they are pooling groups of studies with way too few trials to make any sense and where the likelihood of a meaningful result emerging is small.<br />Second, studies, especially in the brain stimulation area, are repeatedly pooling trials in meta-analyses that really are not equivalent: for example pooling treatments using different types of stimulation or targeting different brain regions. If you pool the results of different treatment approaches, the results of this analysis really cannot have sensible meaning. It cannot say that any of the individual approaches are effective, just that somehow, overall, the approach might be useful. However, non specialist readers will not understand the often subtle differences in how these treatments are applied and may well incorrectly conclude that a true effect has been established.<br />I suspect this later issue is exacerbated by the conduct of analyses by researchers without sufficient &lsquo;domain area&rsquo; expertise: the conduct of meta-analyses by individuals with expertise in the statistical technique but not the treatment being investigated. This seems to be a common problem in the brain stimulation field where the subtleties of different forms of TMS or tDCS may not be obvious to a non-expert. If you don&rsquo;t fundamentally understand the treatment, selecting equivalent and comparable studies may well be impossible.<br />The pooling of studies inappropriately is most likely to lead to a conclusion that a treatment is effective when this conclusion is problematic. The first issue I raised &ndash; the conduct of meta-analyses on too few studies &ndash; has the opposite problem: it is likely to demonstrate a lack of effect, that the treatment does not work. This can have very really world consequences.<br />There is a perfect example of this in my field, especially in the early development of TMS as a therapy for depression. In the early 2000&rsquo;s I was desperately trying to get grant funding to support my TMS research program. However, in 2003 a meta-analysis was published in the British Journal of Psychiatry, of rTMS studies conducted up until that time.&nbsp; This paper included 14 studies, a seemingly reasonable number, but with only 12 studies and 217 patients in the main analysis. Almost all of these were small preliminary studies which provided treatment for extremely short periods of time, some for only one week, to very small numbers of patients (9 studies with 20 or fewer patients). Almost all of these was meaningfully underpowered to show substantive clinical differences.<br />In reality, alone or in combination, the studies were really inadequate to say&nbsp; anything meaningful about the effectiveness of TMS treatment.&nbsp; This was exacerbated by the variability in the studies: they meaningfully differed in treatment dose, duration and the meta-analysis even included one study, the only one with more than 50 patients, where TMS was applied with a substantially different frequency and to the opposite side of the brain.<br />Surprisingly given these limitation, the paper actually found a positive effect of TMS compared to placebo: patients receiving real treatment were better off after 2 weeks of treatment. &nbsp;However, the authors then reported that there was no evidence of efficacy at two week follow up. This finding was prominent in the abstract but with no mention that is was based on only 3 studies, of only 6, 22 and 35 patients. The authors then concluded that there was &ldquo;<em>insufficient evidence to support the use of rTMS on the treatment of depression</em>&rdquo; in what would be the most read part of the paper, the conclusion of the abstract.<br />This would be fine if the results of this study were interpreted appropriately: it showed that there was insufficient evidence to support the antidepressant use of TMS at that time. However, there was certainly a really interesting signal that this could prove to be a highly novel antidepressant strategy. &nbsp;If the field wanted to progress, much more substantive trials were needed.<br />However, this meta-analysis was not interpreted this way. Repeatedly I saw it interpreted as having found that <em>TMS did not work</em>, not <em>that the studies were at that time inconclusive.</em> This had important consequences.<br />When submitting grant applications to obtain funding to hopefully conduct some of these more substantial studies, I repeatedly received rejections citing this meta-analysis as evidence that TMS did not work and therefore did not warrant the conduct of further research. I was persistent enough (read bloody minded perhaps) to push on long enough until I eventually had some success and soon saw the real world clinical impact of TMS on the lives of patients with depression but I wonder how many studies failed to progress because of this issue around the world. For at least a decade after this paper was published, despite TMS being approved for use in the US and being used around the world, I was still hearing people say that this one meta-analysis proved that TMS was not effective, just a waste of time.<br />So where does this leave us? It leaves us in a place where we need to be cautious. These studies should be done as carefully and rigorously as all research and should not be the subject of subtle preferential publication to boost citation metrics for journals.&nbsp; Reviewers, editors and most importantly authors need to be vigilant to carefully and honestly present findings and be especially cautious with the publication of underpowered analyses: the question needs to be asked if the analysis is really justified. Consider whether you would be better off actually trying to collect meaningful data to help prove whether something works or not instead of publishing an underpowered and misleading meta-analysis.</font></div>]]></content:encoded></item><item><title><![CDATA[The Challenges of Depression Treatment in 2020]]></title><link><![CDATA[https://www.paulbfitzgerald.com/blog/the-challenges-of-depression-treatment-in-2020]]></link><comments><![CDATA[https://www.paulbfitzgerald.com/blog/the-challenges-of-depression-treatment-in-2020#comments]]></comments><pubDate>Wed, 03 Jun 2020 12:16:37 GMT</pubDate><category><![CDATA[Uncategorized]]></category><guid isPermaLink="false">https://www.paulbfitzgerald.com/blog/the-challenges-of-depression-treatment-in-2020</guid><description><![CDATA[       Over recent years there has been a laudable and impressive effort to reduce the stigma associated with mental health conditions such as depression, and to engage more people with these conditions in treatment, especially here in Australia. However, this has not been accompanied by a clear reduction in the consequences of depression, such as suicide, in our community. There are lots of possible reasons for this failing but a completely under-recognised one concerns the limited effectivenes [...] ]]></description><content:encoded><![CDATA[<div><div class="wsite-image wsite-image-border-none " style="padding-top:10px;padding-bottom:10px;margin-left:0;margin-right:0;text-align:center"> <a> <img src="https://www.paulbfitzgerald.com/uploads/1/2/6/0/126089503/drowning-sun-1384023-1918x1491_orig.jpg" alt="Picture" style="width:auto;max-width:100%" /> </a> <div style="display:block;font-size:90%"></div> </div></div>  <div class="paragraph"><font size="3"><span style="color:rgb(42, 42, 42)">Over recent years there has been a laudable and impressive effort to reduce the stigma associated with mental health conditions such as depression, and to engage more people with these conditions in treatment, especially here in Australia. However, this has not been accompanied by a clear reduction in the consequences of depression, such as suicide, in our community. There are lots of possible reasons for this failing but a completely under-recognised one concerns the limited effectiveness of the treatments we currently have available.</span><br /><span style="color:rgb(42, 42, 42)">Whilst there are also issues with access to, and the effectiveness of, psychological treatments, I want to focus here on the limitations of existing antidepressant medication treatments. I want to make really clear up front that some patients are helped extremely well by these medications, they can change the lives of patients who respond to them, restoring their ability to function and lead fulfilling lives.</span></font></div>  <div>  <!--BLOG_SUMMARY_END--></div>  <div class="paragraph"><font size="3">If you are taking one of these medications, what I am writing is not meant to persuade you to stop the medication, not at all, don&rsquo;t do this! If your medication is not working, however, talk to your doctor and make sure you actively explore what other options you have. You should set the bar high and aim to get well, to get your old life back.<br />The main problem with antidepressant medication I want to highlight is that they are just not effective for enough people and this limits the size of the group of people who can get the life changing benefits from them that they deserve.<br />The largest study that has investigated the effects of antidepressants was the sequenced treatment alternatives to relieve depression (STAR*D) study <a href="#_ftn1">[1]</a>. This impressive effort was funded by the National Institute of Mental Health in the US, independent of the pharmaceutical industry. It involved the sequential treatment of several thousand patients with depression who received up to 4 different steps of treatment, starting with the standard SSRI antidepressant citalopram. The study examined remission rates: the percentage of the patients who effectively got better with each stage of treatment. In the first round of treatment, ~ 37% of patients became symptom free taking citalopram, only about 30% to the second medication they tried, less than 15% to the third and only 13% to the fourth. There were also significant rates of withdrawal from treatment at each level: 21% after stage 1, 30% after stage 2 and 42% after stage 3.<br />Although these statistics are concerning, they don&rsquo;t quite paint a picture as to how bad things were as overall outcomes are determined both by whether you get better on a medication, but also how long this benefit lasts. Unfortunately relapse, a return of depression, was quite common. It was especially striking that patients who had struggled to get better initially, especially those who needed more than one medication to do so, experienced relapse at quite high rates. In fact, if a patient was in the group who didn&rsquo;t respond to the first medication but then did get better, there was a greater than 50% chance that they would relapse in the next 12 months. Relapse rates were even higher if patients had required three or four courses of initial treatment.<br />It is possible to take these rates and to estimate the chance that a patient will respond and then remain well over a period of time: the overall value of the medication. In a paper published in 2016, Harold Sackeim did this with data from the STAR*D study <a href="#_ftn2">[2]</a>. His analysis found the following. The chance you would get better with the first medication, citalopram, and stay well for 12 months was about 27%. However, if a patient failed to respond to 2 initial antidepressant medication trials, the likelihood that they would respond to a subsequent medication trial and then remain well for at least 12 months fell to less than 5%. In other words, once a patient has failed to respond to 2 medications, the likelihood that they will achieve sustained benefit with the third or subsequent medication is going to be less than one in 20.<br />These results are really sobering and should be a siren call for attention and action. Clearly some patients do wonderfully well with treatment but many don&rsquo;t and once a few medications have failed, the chances of persistent response to future trials falls substantially. This has several direct and important implications.<br />First, we need to think more creatively in the treatment of patients who are not getting better with initial medication treatment. Consider other options, things like repetitive transcranial magnetic stimulation (rTMS) - my hobby horse and clearly an effective option in medication non responsive patients - , other forms of psychotherapy and even ECT. If medication treatment is being pursued and especially if the patient has responded, they need to be followed really closely. Everything that is possible from biological, psychological and social perspectives needs to be done, for example mindfulness based cognitive behavioural psychotherapy, to reduce their risk of relapse over time.<br />Most critically we desperately need a broader range of new accessible and affordable therapies. This is going to take meaningful investment in experimental therapeutics, clinical trials and translational infrastructure. However, our patients really deserve that this be taken as seriously as the other major health problems in our community that attract widespread investment.</font><br /><br /><font size="3">[1] https://www.nimh.nih.gov/funding/clinical-research/practical/stard/allmedicationlevels.shtml<br />[1] Sackeim H. Acute continuation and maintenance treatment of Major depressive episodes with transcranial magnetic stimulation. <em>Brain Stimulation</em> 9 (2016) 313 &ndash; 319</font></div>]]></content:encoded></item></channel></rss>