Depressive disorders are among the most frequent illnesses worldwide. The causes are complex and to date only partially understood. The trace element lithium appears to play a role.
Using neutrons of the research neutron source at the Technical University of Munich (TUM), a research team has now proved that the distribution of lithium in the brains of depressive people is different from the distribution found in healthy humans.
Lithium is familiar to many of us from rechargeable batteries. Most people ingest lithium on a daily basis in drinking water. International studies have shown that a higher natural lithium content in drinking water coincides with a lower suicide rate among the population.
Physicists and neuropathologists at the Technical University of Munich joined forensic medical experts at Ludwig-Maximilian-University of Munich (LMU) and an expert team from the Research Neutron Source Heinz Maier-Leibnitz (FRM II) to develop a method which can be used to precisely determine the distribution of lithium in the human brain.
The team hopes to be able to draw conclusions for therapy as well as to gain a better understanding of the physiological processes involved in depression.
Neutrons detect the slightest traces of lithium
The scientists investigated the brain of a suicidal patient and compared it with two control persons. The investigation focused on the ratio of the lithium concentration in white brain matter to the concentration in the gray matter of the brain.
In order to determine where how much lithium is present in the brain, the researchers analyzed 150 samples from various brain regions – for example those regions which are presumably responsible for processing feelings. At the FRM II Prompt Gamma-Ray Activation Analysis (PGAA) instrument the researchers irradiated thin brain sections with neutrons.
“One lithium isotope is especially good at capturing neutrons; it then decays into a helium atom and a tritium atom,” explains Dr. Roman Gernhäuser of the Central Technology Laboratory of the TUM Department of Physics.
The two decay products are captured by detectors in front of and behind the sample and thus provide information on where exactly the lithium is located in the brain section.
Since the lithium concentration in the brain is usually very low, it is also very difficult to ascertain. “Until now it wasn’t possible to detect such small traces of lithium in the brain in a spatially resolved manner,” says Dr. Jutta Schöpfer of the LMU Munich Institute for Forensic Medicine.
“One special aspect of the investigation using neutrons is that our samples are not destroyed. That means we can repeatedly examine them several times over a longer period of time,” Gernhäuser points out.
Significant difference between depressive patients and healthy persons
“We saw that there was significantly more lithium present in the white matter of the healthy person than in the gray matter. By contrast, the suicidal patient had a balanced distribution, without a measurable systematic difference,” summarizes Dr. Roman Gernhäuser.
“Our results are fairly groundbreaking, because we were able for the first time to ascertain the distribution of lithium under physiological conditions,” Schöpfer is glad to report. “Since we were able to ascertain trace quantities of the element in the brain without first administering medication and because the distribution is so clearly different, we assume that lithium indeed has an important function in the body.”
Just a beginning
“Of course the fact that we were only able to investigate brain sections from three persons marks only a beginning,” Gernhäuser admits. “However, in each case we were able to investigate many different brain regions which confirmed the systematic behavior.”
“We would be able to find out much more with more patients, whose life stories would also be better known,” says Gernhäuser, adding that it might then also be possible to answer the question as to whether the deviating lithium distribution in depressive persons is a cause or a result of the illness.
Funding: The research work was funded by the German Research Foundation (Deutsche Forschungsgemeinschaft; DFG). Scientists from the Institute for Forensic Medicine at Ludwig Maximilian University of Munich as well as from the TUM Institute of Pathology and TUM Department of Physics took part in the research.
The research neutron source Heinz Maier-Leibnitz (FRM II) provides neutrons and positrons for research, industry and medicine. Operating as a user facility for up to 1200 guest scientist per year, the Heinz Maier-Leibnitz Zentrum (MLZ) offers a unique suite of high-performance neutron scattering and positron instruments. The MLZ is a cooperation of the Technical University of Munich, the Forschungszentrum Jülich and the Helmholtz-Zentrum hereon.
In this study, we examined treatment patterns in a cohort of 197,615 patients diagnosed with MDD at Danish hospitals between 1996 and 2015. We found that most patients with MDD initiated treatment with an SSRI during the assessment period and those that switched treatment most often shifted to another SSRI or an SNRI. SNRIs were most often the TRD-defining treatment and 37% of patients with TRD shifted to a fourth treatment or more. Treatment patterns were not dependent on depression severity nor year of diagnosis, except for increasing rates of antipsychotics and psychotherapy over the study period.
Our study also showed that existing guidelines (American Psychiatric Association, 2010; Danske Regioner, 2016; “NICE. Depression in adults: recognition and management,” 2009) for first-line treatment seem to be followed for most MDD patients, with SSRI being the most frequently used first-choice drug during the whole study period. However, currently there is limited guidance for treatment of patients with TRD (MacQueen et al., 2017).
The Danish guideline describes that MAOI might be indicated in patients with TRD and that lithium is considered first choice in treatment resistant patients to prevent development of bipolar disease (Danske Regioner, 2016). APA also consider MAOI to be exclusively reserved for TRD and describes transcranial magnetic stimulation, vagus nerve stimulation and ECT as potential treatment of TRD (American Psychiatric Association, 2010).
The two latter treatments options were not offered during follow-up of this study. Our study shows that most patients either do not initiate any further treatment with antidepressants or ECT (63.0%) or mainly shift between SNRI and SSRI within one year after meeting the criteria for TRD. As such, no systematic pattern in choice of treatment modalities was evident. This possibly reflects that treatments become more individualized when patients do not benefit from standard treatment.
However, our findings could also reflect that no specific guidance is offered for TRD in the Danish guidelines, which may lead to individualized treatment based on the subjective preferences of the psychiatrist or patient that may or may not always be evidence-based treatment choices. Recent studies (Adli et al., 2017; Bauer et al., 2019) have shown that algorithm-guided treatment of MDD may lead to better outcomes than treatment as usual, which underlines the need for both treatment-specific guidelines and the importance of adhering to these.
The lack of systematic pattern in choice of treatment modalities could also be explained by off-label drug use by psychiatrists, e.g. antiepileptics not covered by our analyses. Lastly, though not included in our definition of TRD, augmentation and psychotherapy are also part of treating MDD. Patients not progressing from third treatment might have initiated augmentation or psychotherapy alongside antidepressant treatment before starting a new antidepressant treatment shift.
In line with this, our findings suggest that approximately 15% of patients meeting the TRD criteria initiate treatment with antipsychotic agents within one year after TRD diagnosis. Correspondingly, results from a clinical cross-sectional European multicenter study investigating pharmacological treatment strategies in 1,181 MDD patients showed that 24.2% of patients were prescribed at least one antipsychotic drug in addition to ongoing antidepressant medication (Dold et al., 2016).
Atypical antipsychotic augmentation is an established approach in the pharmacotherapy of TRD and might have been used to target residual symptoms such as sleeping disturbances or minimize side-effects, and they have increasingly been used since the introduction of quetiapine to Denmark in the early 2000s.
The main reasons for the fluctuations in the use of psychotherapy is because its registration was not complete in the registers during the first study period. Further, information on the use of private psychotherapists is not available in the registers.
It is noteworthy, that only minor differences in treatment patterns were observed when grouping patients according to the severity of their depression, as we would have expected that patients with severe depression had other modalities of treatment, e.g. TCA, MAOI, or ECT as recommended in existing treatment guidelines (American Psychiatric Association, 2010; Bauer et al., 2017; Danske Regioner, 2016; “NICE.
Depression in adults: recognition and management,” 2009). Actually, 8.6% of the patients with severe depression included in our cohort never initiated any of the included treatments during one year prior to one year after MDD diagnosis. This might be explained by low registration of ECT during the first part of the study period and missing information on drug administration during hospitalization. On the other hand, one would expect that patients would continue treatment after discharge and have redeemed prescriptions from the community pharmacy, thus be registered in the National Prescription Registry. Further, we only considered the lack of information on drugs administered during hospitalization to be a minor problem since previous analyses did not reflect these concerns (Gronemann et al., 2018).
With regard to first-line treatment, our study is in accordance with previous studies from five European countries including Denmark, Germany, the Netherlands, Spain, and the UK (Abbing-Karahagopian et al., 2014), showing that SSRIs are the most commonly prescribed antidepressants. Few studies have examined treatment patterns following first-line treatment. A study from a primary care database in the UK following 262,844 patients who initiated antidepressant treatment between 2005 and 2011 (Mars et al., 2017) found that most patients with MDD initiated treatment with an SSRI (87%) and that 9% of patients switched to another antidepressant, prevailingly another SSRI.
A Japanese study following 1,592 MDD patients identified in a health insurance claims database found that 17% of patients with a first-time treatment switched to another antidepressant after an average of 3 months (Furukawa et al., 2013). The proportion of patients switching antidepressant treatment in these studies (Furukawa et al., 2013; Mars et al., 2017) is much lower than in the present study, in which more than 50% of MDD patients switched from a first to a second treatment.
These differences could be due to our cohort representing a population with a hospital contact with MDD, whereas the UK and Japanese cohorts were from the general population. Our study analyzed patients with a first-time hospital contact for depression and therefore might not have included the presumed milder cases of depression, as they are only treated in primary care in Denmark.
Findings from the clinical cross-sectional European multicenter study by Dold et al. (2016) yielded a slightly higher proportion, 29% of patients received at least one adjunctive antidepressant in addition to their first line therapy (Dold et al., 2016). Here patients were recruited in both in- and outpatient clinics, which is closer to the setting of our study.
In the Oklahoma Medicaid Claims Database, Hassan et al (2016) identified 1,797 adults diagnosed with unipolar depression who had initiated secondary antidepressant treatment between 2006-2011 (Hassan et al., 2016). In this population, the most frequent secondary treatment was atypical antipsychotics augmentation (51%), 25% received other augmentation (lithium, triiodothyronine, buspirone), and 23% received two combined antidepressants.
Similarly, in the clinical cross-sectional European multicenter study, 24.2% of patients were treated with antipsychotic augmentation, 10.1% received mood stabilizer augmentation (lithium, valproate or lamotrigine), while 33.2% of patients received add-on treatment with benzodiazepines or related substances (Dold et al., 2016).
One US-based study characterized differences in treatment patterns between TRD and non-TRD episodes in MDD patients (Kubitz et al., 2013). In this study, 82,742 MDD patients were identified in the US PharMetrics Integrated Database, 52% of MDD episodes were not treated with pharmacotherapy and 6% were defined with TRD (two distinct failed treatments).
SSRIs were the most frequently used drug class for both TRD and non-TRD episodes, comprising more than 60% of the treatments. Usage of all other drug classes, such as SNRI, TCA, atypical antidepressants (buspirone), and concomitant antipsychotics was more prevalent for TRD than for non-TRD episodes. Surprisingly, ECT did not seem to be included in the analyses. Also, there was a large proportion of non-treated patients in this study, which can indicate that the cohort included many milder cases of depression, which is not very representative of our cohort. Finally, 12.3% of patients did not initiate treatment with either antidepressants or ECT. However, they could have initiated psychotherapy or other treatment options. Further, 3,177 patients died, and 29 patients emigrated within 30 days after MDD diagnosis leading to no registration of redemption of antidepressants within Danish registers.
There are some strengths and limitations to our study that must be taken into consideration when interpreting the results. An advantage was the use of population-based registers in a country with a tax-based national health care system, which minimizes the risk of selection bias. Further, the registers contain documentation of diagnoses that are based on clinical assessments, which, in turn, reduces the risk of misclassification of the population.
Additionally, the unique personal identification number that all Danish citizens are assigned allowed us to link individual patient data with other registries to obtain complete follow-up information for the purchase of medicine, hospital treatments, migration, and death. Thus, the registers ensure a complete follow-up, reduce the potential for selection bias, and increases the validity of this study.
A limitation applicable to many studies using treatment algorithms to identify disease is whether the applied method captures all patients intended. In our study some of the shortcomings are the lack of information on why patients changed antidepressant treatment (e.g. lack of efficacy, adverse events, or patient’s choice) and there were no measures of treatment adherence.
However, in sensitivity analyses, we explored the effect of treatments lasting less than 4 weeks (and possible alterations due to side effects) and treatment gaps of more than 6 weeks (based on dose and number of refills) and their influence on associations of depression-related covariates with TRD.
These analyses showed that this was not the case (Gronemann et al., 2018). It has also been shown that more restrictive definitions of TRD result in slightly lower proportions of patients with TRD, but overall it does not change the pattern of associations with risk factors and outcomes (Hägg et al., 2020).
Another limitation of our definition of TRD is that we did not incorporate augmentation approaches. However, the Danish treatment guidelines first recommend antipsychotic or lithium augmentation as a 4th option after 3 failed antidepressants so it should not affect the TRD definition per se. Thus, it is expected to have limited impact on the definition of treatment resistant depression.
Although prescriptions were redeemed and paid for, we cannot be certain that the patients ingested the medicines. However, because the Danish National Prescription Register holds information on redeemed prescriptions, we do know that the patient purchased the drugs and hence the medication can be considered one step closer to ingestion than in studies investigating data on prescriptions only.
Furthermore, information on drug administration for hospitalized patients was not available; and use of ECT, as well as of psychotherapy, was not fully registered before 2001 (Hundrup et al., 2017). Moreover, our study was based on patients with a first-time hospital contact with depression and therefore the treatment patterns might not be similar in the presumed milder cases of depression mainly treated in primary care in Denmark.
Consequently, though we included patients at their first-time hospital contact, it might not reflect the first time the patient presented with depression since milder episodes of depression in the patient could have been treated at the general practitioner. The validity of depression severity in the DNPR has been shown to be low for milder cases (Bock et al., 2009) and we cannot exclude that misclassification has made it difficult to detect small differences in treatment.
In this study, patients were sampled at first hospital contact with depression. This may lead to a higher mean age at first depression diagnosis than in studies using prescription data only. Using prescription data only, however, comes with some limitations since indication for antidepressant use was not available in the Danish National Prescription Register during the study period.
Hence, using this approach we would not have been able to distinguish whether antidepressants were prescribed for other conditions than depression. Finally, the project was ended in 2016 and did not include newer antidepressant treatments introduced, such as esketamine.
In conclusion, we find that 15% of patients with a hospital contact with MDD meet the TRD criteria. Irrespective of depression severity or TRD, SSRIs, and SNRIs are the most commonly used antidepressant treatments for depression in Denmark, administered in different order. Our findings confirm that the guidelines for first treatment of MDD seem to be followed for most patients, whereas treatment of patients meeting the TRD criteria is arbitrary, possibly due to lack of specific guidelines.
reference link :https://www.sciencedirect.com/science/article/pii/S0165032721002548?via%3Dihub
Original Research: Open access.
“Position sensitive measurement of trace lithium in the brain with NIK (neutron-induced coincidence method) in suicide” by J. Schoepfer, R. Gernhäuser, S. Lichtinger, A. Stöver, M. Bendel, C. Delbridge, T. Widmann, S. Winkler & M. Graw. Scientific Reports
