Lithium for Depression.....

I bought a copy of Manic Depressive Illness when it first came out in 1990.  One of the more interesting aspects of the book was the commentary on the use of lithium monotherapy for unipolar depression.  That discussion is limited to about three pages and reviewed the work to date.  In the opening paragraph there is this astonishing line:  "Overall, the result of open studies suggest that lithium is as effective in preventing unipolar illness as it is in preventing bipolar illness."  At the time there were 4 controlled studies (3-6) looking at the issue of maintenance therapy in mixed unipolar and bipolar groups.  Three of the four studies showed no difference between groups.  The fourth study was inconlusive due to a high dropout rate.  Subsequent analyses by Schou and Baldessarini and Tohen concluded that the protective effects of lithium in preventing recurrent depressive episodes was good.  In Schou's reanalysis he showed that the relapse rate in one year on lithium for unipolar depression was 22% (compared with a 20% relapse rate for bipolar disorder) and the rates for antidepressants at one year were 35% for unipolar depression and 65% for bipolar disorder (relative to placebo of 67-68% relapse rate).

Since that early open research there has been only randomized controlled clinical trial (RCT) of lithium versus placebo antidepressant augmentation (7).  In that study 7/15 patients treated with placebo relapsed and one suicided.  In the lithium treated group 0/14 relapsed.  The authors recommended that patients who respond to lithium augmentation be maintained on it for at least 6 months.  Additional clinical parameters of interest in the treated group was an average lithium dose of 980 mg, an average Li level of 0.65 mmol/L, and a response time of 17.5 days in acute treatment.  This is interesting because many psychiatrists using lithium augmentation were taught to stop at 600 mg/day and accept the associated lower levels.

My point in the introductory paragraph here is that it has been known for some time that lithium may have a role in maintenance of unipolar depression in addition to bipolar depression - even though it is hardly ever used that way int he United States.  In the US, patients typically endure a long series of antidepressant trials or augmentation strategies if the initial trails are ineffective.  There is always the problems of whether the antidepressant has lost its effect or not and the associated difficulty of trying to determine what other factors may be operative.  Lithium has been used for the past three decades as an augmenting agent - added to antidepressants.  Typically a lower dose is used (600 mg/day) and that may offer a lower chance of toxicity and less need for monitoring blood levels.

Against this backdrop, a very interesting paper by Tiihonen, et al came out last year (2). For reasons that will follow, I consider this to be one of the most important papers for clinical psychiatrists from 2017.  The authors provide a sound rationale for their study, specifically the advantages of a large scale epidemiological/observational study over an RCT or the Cochrane meta-analysis of RCTs.  That meta-analysis (like most Cochrane meta-analyses) concluded that the number of subjects included was too small to come to a statistically significant conclusion.

The study was conducted in Finland.  The authors point out that each citizen has a unique identifier that facilitates the design of large inclusive observational studies across health care databases.  The sample in this case was a study cohort (N= 123,712) of patients who had been admitted to a hospital for unipolar depression between January 1, 1987 and December 31, 2012.  They had a comparison incident cohort (N=30004) that looked at new patients beginning on December 31, 1996 with no mental health diagnosis, hospital admissions for depression, exposure to the medications of interest, or history of outpatient care in the year prior to the start.  The purpose of the incident cohort was to look at the issue of survival bias. The primary outcome measure was risk of readmission in all patients admitted  for unipolar depression at least once between 1987 and 2012.  All cause admissions were a secondary outcome measure.  Medication use was estimated using the PRE2DUP mathematical modelling of the patient medication purchasing.  Each patient was used as their own control to eliminate selection bias.  I did not have access to the appendices from this study, so I will forgo further discussion of the statistical methodology without that data.

Mean hospitalizations for people who had used lithium was 4.3 (SD 6.9) for psychiatric admission and 7.8 (SD 9.1) for all cause admissions compared to 2.2(SD 3.1) and 5.8(SD 7.0) for those who had not indicating the lithium treated patient were more severely ill.  Using lithium significantly decreased the relapse risk.  Mean daily lithium dose was noted to be 765 mg.  Forest plots are contained in the body of the article looking at the hazard rations of readmission for several pharmacological treatments in both the study cohort and the incident cohort.  Forest plots looked at benzodiazepines, hypnotics, antipsychotics, and lithium +/- antidepressants.

Lithium monotherapy was superior to all other studied pharmacotherapies in preventing hospital readmissions.  Older antidepressants (amitriptyline and doxepin) and antipsychotics (clozapine sulpride, aripiprazole, and quetiapine) showed some efficacy in preventing hosptializations.  Benzodiazepines did not.  In the incident cohort where (survival bias was eliminated) the lithium effect on decreased rehospitalizations was more robust suggesting the effect size was more valid than for the total cohort.  They also did a secondary mortality assessment and showed that both lithium and antidepressants were associated with decreased overall mortality and no difference was observed for antipsychotics.

The authors recognize that there are significant adverse effects and limitations with the use of lithium.  They point out there are also possible advantages outside the treatment of mood disorders but there is a significant burden associated with taking it.  They recommend that is be considered for maintenance of a broader group of patients with unipolar depression.  In our antidepressant-centric society, I agree with their conclusion.  The effects in this study really cannot be ignored.  Lithium augmentation of antidepressants has been around for over 30 years.  It surfaced again the the STAR*D protocol.  I see patients who have been exclusively been treated by other physicians or prescribers and in the past 8 years I have seen exactly 1 patient with unipolar depression who was being treated with lithium augmentation.  It is far more common to see patient taking 2-4 antidepressants (typically SSRI + bupropion + trazodone or mirtazapine) or an antidepressant plus lamotrigine as the augmentation strategy.  A similar study with a cohort of American patients would be very useful to look at questions about the efficacy of lithium versus the antidepressant polypharmacy or lamotrigine - but my concern would be that there would not be a large enough sample of patients taking lithium.

It may be up to clinicians who are used to lithium therapy and the application to unipolar depression to reintroduce the practice and collect data on what the outcomes are relative to standard antidepressant augmentation strategies. Overall this study from a group of pharmacoepidemiologists provides compelling data to take a second look at an old strategy instead of just adding more antidepressants.  The data looks so good, lithium is so inexpensive, and in the USA we are in an absolute vacuum of lithium non-use for unipolar depression.   Inpatient treatment for depression has become so atrocious that it has never been more important to help people stay out of the hospital. That is why I considered this to be an important paper. 


George Dawson, MD, DFAPA

       

References:

1:   Goodwin, FK, Jamison, KR. Manic-depressive illness. New York: Oxford University Press, 1990: pp.693-696.

2: Tiihonen J, Tanskanen A, Hoti F, Vattulainen P, Taipale H, Mehtälä J,Lähteenvuo M. Pharmacological treatments and risk of readmission to hospital for unipolar depression in Finland: a nationwide cohort study. Lancet Psychiatry. 2017 Jul;4(7):547-553. doi: 10.1016/S2215-0366(17)30134-7. Epub 2017 Jun 1. PubMed PMID: 28578901.

3: Prien RF, Klett CJ, Caffey EM Jr. Lithium carbonate and imipramine inprevention of affective episodes. A comparison in recurrent affective illness. Arch Gen Psychiatry. 1973 Sep;29(3):420-5. PubMed PMID: 4579507.

4: Prien RF, Caffey EM Jr, Klett CJ. Prophylactic efficacy of lithium carbonate in manic-depressive illness. Report of the Veterans Administration and National Institute of Mental Health collaborative study group. Arch Gen Psychiatry. 1973 Mar;28(3):337-41. PubMed PMID: 4569674.

5: Coppen A, Noguera R, Bailey J, Burns BH, Swani MS, Hare EH, Gardner R, MaggsR. Prophylactic lithium in affective disorders. Controlled trial. Lancet. 1971 Aug 7;2(7719):275-9. PubMed PMID: 4104974.

6: Baastrup PC, Poulsen JC, Schou M, Thomsen K, Amdisen A. Prophylactic lithium: double blind discontinuation in manic-depressive and recurrent-depressive disorders. Lancet. 1970 Aug 15;2(7668):326-30. PubMed PMID: 4194439.

7: Bauer M, Bschor T, Kunz D, Berghöfer A, Ströhle A, Müller-Oerlinghausen B.Double-blind, placebo-controlled trial of the use of lithium to augment antidepressant medication in continuation treatment of unipolar major depression. Am J Psychiatry. 2000 Sep;157(9):1429-35. PubMed PMID: 10964859.


Supplementary:

Figure 1 above is directly from reference 2 with permission from Elsevier.  Licensing agreement #4270040486127.

If Your Patient Really Needs Lithium.......

I had the good fortune to work in an intense medical setting for about 22 years where I was responsible for the medical care of my patients.  In that setting I had access to excellent specialists, in fact some of the finest physicians I have seen anywhere.  They were typically involved when I had identified a medical problem that potentially complicated the psychiatric care of my patients.  In those cases - no matter what the problem was it usually came down to the question: "If your patient really needs this medication we need to continue it."  One of the most significant complications was renal failure of varying degrees while taking lithium.  Some patients on my unit were hospitalized because they had been stable on lithium but were developing renal failure and needed to be tried on another agent.  In some cases they experienced severe associated complications including delirium either from the bipolar disorder or medications used in the transition.  In some cases, they needed dialysis and renal medicine consultants would advise me on the lithium dose to try while they were receiving hemodialysis.  All of this experience led me to have a very low threshold for recognizing and acting on potential adverse effects of lithium as early as possible. 

At various points in my career, there was a question of renal failure occurred in cohorts on lithium or it was due to a different cause.  As an example, the Lithium Encyclopedia from 1983 (1) stated concisely: "There have been a growing number of reports of morphological and functional kidney damage associated with lithium use.  The actual incidence of lithium nephrotoxicity is not known.  Most researchers believe that irreversible damage is not widespread but that risk increases with length of treatment and serum lithium level."

At the time there were opinions that up to 20% of patients on long term lithium maintenance had morphological changes and functional changes primarily with water absorption but no reduced glomerular filtration rate (GFR) or renal insufficiency.  My favorite renal and electrolyte disorders text cited lithium as a compound that caused vasopressin resistant nephrogenic diabetes insipidus (NDI) (2).  More recent evidence suggests that 15-20% of patients on lithium develop a progressive decrease in GFR typically does not progress to end stage renal disease (ESRD) and dialysis but in some cases it clearly does.  These generalizations are usually based on low numbers of patients who have been identified as having a specific creatinine or GFR.  A creatinine of 2.5 mg/dl predicted progression to ESRD in most patients.  A larger study in Sweden of 3369 patients, suggested a lower threshold. In that study,  13 patients had been off lithium for 2 years before starting dialysis and 11 had a creatinine of > 1.4.  Some were lower but there had been a progressive increase from baseline suggesting the rate of change is important.  Additional factors such as the use of NSAIDS and ACE inhibitors like lisinopril as well as other intrinsic kidney diseases can be a factor.

There have been a recent increase in studies that look at the side effects of lithium and in one case (6) compare lithium side effects to other typical mood stabilizers (valproate, olanzapine, questiapine).  One of the studies uses descriptive statistics and the other two involve calculations of hazard ratios for specific risks.  The results are fairly uniform in their conclusions and have been known in most psychiatry training programs for the past 10-20 years.  The articles here use the Kidney Disease Outcomes Quality Initiative (KDOQI) staging of chronic kidney disease published in 2002.   The range is from stage 1 (eGFR ≥ 90 ml/min/1.73 m² ) to stage 5 (eGFR < 15 ml/min/1.73 m² or dialysis).  For the purpose of these papers Stage 2 is an eGFR of 60-89 and Stage 3 is 30-59. As previously noted progression can occur in some cases even years after the lithium has been stopped.

The most interesting of the three papers is probably from Hayes, et al because of their strategy to look at lithium toxicity but in the context of other commonly used mood stabilizers (valproate, olanzapine, quetiapine) and the associated toxicities of these other mood stabilizers.  As a result they have a table entitled Table 2. Adverse effects during maintenance treatment that looks at these mood stabilizers and CKD (stage 3 and 4), hypothyroidism, hyperthyroidism, hypercalcemia, Type 2 diabetes mellitus, cardiovascular disease, hypertension, hepatotoxicity, and weight gain (greater than 7% and greater than 15%).  Hazard ratios care calculated for all of these adverse effects using lithium as the reference.  The number of events in each category is relatively low compared with the total events in a large clinical sample.  The adverse events described were expected.  They estimated the rate of severe CKD (stage 4 or 5) as 1 in 100 person years at risk.  The estimated rates of stage 3 and stage 4 CKD were 9 in 100 per years at risk.  Hepatotoxicity was rare in the sample and was elevated in the quetiapine group.  Weight gain was most significant for olanzapine, quetiapine, and valproate relative to lithium.  Olanzapine also had the highest rate of new onset hypertension.

None of this information deters me from offering lithium to people who I think are good candidates.  The rationale is that lithium can be a life changing medication, especially for people who have generally never achieved mood stabilization with all of the typical medications prescribed for mood disorders these days.  Informed consent should include this potential complication.  I generally advise people that there is a 40% risk of NDI of varying severity, the need for ongoing testing, the need to avoid additional medications that may complicate the use of lithium, and finally close self monitoring of both side effects and any situation that can complicate lithium therapy like conditions leading to dehydration.  I will add the risk of mild CKD and explain to the patient what that means.

One of the interesting aspects of these articles is that ongoing screening for patients on lithium therapy varies considerably from setting to setting.  National guidelines seem to help.  In these large scale studies there is not enough discussion of work at the clinical level incorporating the red flags from the research.  For example it is obviously important to know about new medications, especially ACEIs, NSAIDs, and serotonergic medications.  Medications that may complicate interpretation of lab finding like Vitamin D and Calcium supplementation in the case of hypercalcemia are also important.  The review of systems is also important anywhere along the spectrum of side effects including neurological, cognitive, gastrointestinal, and renal symptoms.  I generally advise patients that increasing nocturia, polyuria, and polydipsia with associated laboratory finding increases the risk of irreversible renal changes including a low risk of progression to ESRD.  The presence of edema may indicate the rare onset of a nephrotic syndrome that can occur is some people with acute treatment.

The good news is that even now there is an accumulating literature on the potential complications of lithium therapy and some general ideas about what psychiatrists should do about it.  Although the methodology of these studies varies significantly they generally come to similar conclusions about the effect of lithium on renal function, thyroid function, and calcium metabolism.  All of these systems require close monitoring by assessing the patients clinical status and lab testing.  Numerous changes in clinical status should result in departures from any monitoring routine.  The critical elements is communication with the patient and education about when the psychiatrist should be contacted.
   

George Dawson, MD, DFAPA 


References:

1:  Jefferson JW, Greist JH, Ackerman DL.  Lithium Encyclopedia for Clinical Practice.  American Psychiatric Press, Inc. 1983: p151.  

2:  Schrier RW (ed).  Renal and Electrolyte Disorders, 2nd Ed.  Little, Brown and Company, Inc.  Boston 1980: p. 31.

3:  Lerma VE.  Renal toxicity of lithium. In UpToDate.  Sterns RH, Sheridan AM (eds) (Accessed on January 2, 2018).

4: Bendz H, Schön S, Attman PO, Aurell M. Renal failure occurs in chronic lithiumtreatment but is uncommon. Kidney Int. 2010 Feb;77(3):219-24. doi: 10.1038/ki.2009.433. Epub 2009 Nov 25. PubMed PMID: 19940841. (see open access text).

5:  Dineen R,  Bogdanet D,  Thompson D, Thompson CJ,  Behan LA,  McKay AP, Boran G,  Wall C, Gibney J, O’Keane VO, Sherlock M.   Endocrinopathies and renal outcomes in lithium therapy: impact of lithium toxicity.  QJM: An International Journal of Medicine, Volume 110, Issue 12, 1 December 2017, Pages 821–827, https://doi.org/10.1093/qjmed/hcx171

6: Hayes JF, Marston L, Walters K, Geddes JR, King M, Osborn DP. Adverse Renal, Endocrine, Hepatic, and Metabolic Events during Maintenance Mood Stabilizer Treatment for Bipolar Disorder: A Population-Based Cohort Study. PLoS Med. 2016 Aug 2;13(8):e1002058. doi: 10.1371/journal.pmed.1002058. eCollection 2016 Aug. PubMed PMID: 27483368.

7: Shine B, McKnight RF, Leaver L, Geddes JR. Long-term effects of lithium on renal, thyroid, and parathyroid function: a retrospective analysis of laboratory data. Lancet. 2015 Aug 1;386(9992):461-8. doi: 10.1016/S0140-6736(14)61842-0. Epub 2015 May 20. PubMed PMID: 26003379.
    

Lithium and Pregnancy - The Latest From the NEJM

Lithium and pregnancy have always been a major concern for psychiatrists, obstetricians, and of course women who need to take the medication for mood stabilization.  In the Lithium Encyclopedia (published in 1983) - there is a chapter on the physiological effects of pregnancy and how that potentially affects lithium balance and a separate chapter on teratogenesis.  That chapter describes the Lithium Baby Registry that was established in 1970 to collect information on the effects of lithium in pregnancy.  In the first 10 years, 225 infants exposed to lithium were described and 25 had congenital malformations.  Of these births 18/25 had cardiovascular abnormalities including Ebstein's anomaly, 7 were stillborn, 2 had Down's syndrome and 1 had intracerebral toxoplasmosis.  The results suggested that lithium was a cardiovascular teratogen, but there was a question of reporting bias.  That is, results consistent with the study concern about lithium being a teratogen were more likely to be reported than normal births.  

Those references set the knowledge about lithium and  pregnancy for all residents trained in my era in the late 1980s.  The standard question by attendings and on examinations was: "What is the cardiac anomaly associated with intrauterine exposure to lithium?".  The answer was Ebstein's anomaly.  The follow up question was expected: "And what is Ebstein's anomaly?"  In those days the short answer was downward displacement of the tricuspid valve into the right ventricle.  Today Ebstein anomaly (no longer a possessive) is described in greater detail. A modern reference describes the extension of the tricupsid valve into the right atrium to the extent that most of the functional chamber chamber is collapse to a very small volume.  In some cases it is collapsed to the right ventricular outflow tract.  The downward valve displacement is due to a number of morphological abnormalities in the tricuspid valve.  The myocardium is also abnormal because the valve tissue has failed to completely separate from the myocardium during fetal development - a process called delamination.  That is associated with a thin and poorly contractile myocardium and poor right ventricle performance. There are several associated cardiac abnormalities including ventricular septal defect, patent foramen ovale, patent ductus arterious, and accessory conduction pathways that can lead to arrhythmias.  The associated clinical syndromes of cyanosis, congestive heart failure and arrhythmia can occur in infancy to adulthood depending on the degree of anatomical disruption.  The complications can be fatal at any age (2).

Ebstein abnormality is a preventable complication and one that must be avoided.  In real life that is easier to say than do.  In a controlled hospital or clinic environment it is a very straightforward process to take a history and determine the obstetric history and last menstrual period.  Urine and serum pregnancy tests can be done for confirmation.  The best advice to physicians in this situation is to treat very woman of childbearing age as if they were pregnant until proven otherwise.  In my experience life is less regimented.  There are lapses in contraception and planning that lead to pregnancies in women taking lithium who know that exposure to the infant is an avoidable risk.  Many of these women are on lithium maintenance.  Since lithium remains a mainstay of treatment for bipolar disorder and may be a superior agent in postpartum psychosis - the question of teratogenicity remains an important one.

There have been a number of estimates of congenital malformations due to psychiatric medications and I recently reviewed a few of them and cited extensive database references.  In one of the reviews very large databases were examined looking for major congenital malformations to lithium exposed women especially Ebstein anomaly.

The New England Journal of Medicine published another large retrospective database study of the question of lithium exposure in pregnancy and risk of cardiac malformations.  Their database involve a Medicaid cohort of 1,325,563 pregnancies over the ten year period between 2000 and 2010.  In this cohort there were cardiac malformations noted in 16 of 663 (2.4%) lithium exposed infants.  Lower rates of cardiac malformations were noted in nonexposed infants (1.15%) and lamotrigine exposed infants (1.39%).  In addition there appeared to be a dose related effect with increasing risk ratio noted with increasing doses of lithium.  For example at the dose of 600 mg or less/day the risk ratio was 1.11 but the risk ratio increased to 1.11 and 3.22 for doses of 601-900 mg/day and greater than 900 mg respectively.

The authors have a detailed report on how the cardiac malformations were determined.  They make an interesting point that a misclassification bias can occur with Ebstein anomaly.  Some clinicians may make the diagnosis of right ventricular outflow tract obstruction defects or Ebstein anomaly based on whether or not there has been a history of exposure to lithium.  That may make it more likely to misclassify Ebstein anomaly.  They provide data for the total prevalence of all cardiac malformations and cardiac malformations classified as right ventricular outflow obstruction.  They were focused on "major cardiac defects that were likely to be consequential for the infant."  The diagnostic codes had to be listed several times or associated with surgery.

The calculated prevalence of Ebstein abnormality in unexposed pregnancies was 7 cases per 100,000 live births.  They did not provide the prevalence of Ebstein anomaly in the lithium exposed due to the low number.  After a detailed analysis and analysis of possible sources of error like terminate pregnancies where lithium exposure occurred the authors conclude that lithium had a modest effect in terms of increased risk of cardiac malformations.  Their final estimate was an increased risk of 1 additional case per 100 live births if the exposure occurred early in the pregnancy.  They describe this as a modest increase in risk of cardiac malformations due to lithium.  The difference in the ratio of cardiac malformations in this study (16/663) compared with the Lithium Baby Registry (18/225) is probably due to a more rigorous methodology.

The authors looked at five sources of error in their final discussion of the results.  For clinical psychiatrists the most relevant point was that other factors affecting treatment decisions in pregnancy were not investigated.  They are considerable given that it is highly likely that the women being treated with lithium have severe mood disorders and suicide in the postpartum period in the number one cause of death.  This study can best be viewed as a study that supports current clinical practice to avoid first trimester exposure to lithium by careful screening and then planning if additional adjustments need to be made for planned pregnancies based on the trimester.  In those cases of accidental exposure, consultation with high risk obstetrics and a decision based on a detailed discussion with the patient is usually the preferred option.                 




George Dawson, MD, DFAPA




References:

1.  Jefferson JW, Greist JH, Ackerman DL. Lithium Encyclopedia for Clinical Practice.  Washington, DC; American Psychiatric Press, Inc., 1983: 264-265.

2.  Connolly HM, Qureshi, MY.  Clinical manifestations and diagnosis of Ebstein anomaly. In UpToDate,  Greutmann M, Fulton DR, Yeon SB (Accessed on June 9, 2017).

3.  Patorno E, Huybrechts KF, Bateman BT, Cohen JM, Desai RJ, Mogun H, Cohen LS, Hernandez-Diaz S. Lithium Use in Pregnancy and the Risk of Cardiac Malformations. N Engl J Med. 2017 Jun 8;376(23):2245-2254. doi: 10.1056/NEJMoa1612222.

Mechanism Of Action Of Lithium - A Brief History

As a chemistry major and a psychiatrist Lithium has a special place in my consciousness.  During the years that I took organic chemistry lithium aluminum hydride was a favorite reducing agent when creating certain organic syntheses.  Most chemistry majors remember metallic lithium as one of those highly reactive metals that was packed under oil to prevent contact with water or even moisture in the air.  Lithium's reactivity is why the free metal does not exist in nature.  The most common form used as a medication is lithium carbonate in various preparations.

There has been a lot of speculation about the mechanism of action of lithium since its discovery.  Early in my career the definitive source of information for all things lithium-related was the Lithium Information Center at the University of Wisconsin Department of Psychiatry.  It was possible to call them and ask them anything about lithium and get the relevant references sent to you.  They also produced the Lithium Encyclopedia for Clinical Practice.  The mechanism of action was described as unknown at the time but ongoing research was cited (p. 7) in "ion substitution with subsequent effects on amine metabolism, membrane transport, glucose metabolism, and neurotransmitter synthesis and degradation."  An entire chapter was dedicated to mechanism of action.  In that chapter, the review of what was known about the mechanism of action at the time is interesting.  The major neurotransmitter systems being studied at the time were catecholamines, serotonin, and acetylcholine.  Animal studies showed acute changes on norepinephrine turnover that was only slight to non-existent with chronic use.  Results on serotonin turnover were conflicting, but it prevented hyperaggressive behavior resulting from a serotonin depleting compound that blocked tryptophan hydroxylase (parachlorophenylalanine).  Acute administration did not alter dopamine turnover.  Chronic administration resulted in increased turnover in mesolimbic and striatal areas but not the cortex.  These observations led to theories that lithium worked by altering post synaptic receptor sensitivity including decreased beta adrenoreceptor effects, stabilized opioid receptors, and preventing dopamine receptor hypersensitivity.

There was some speculation about endocrine mechanisms since it was known that lithium blocks release of thyroid hormone (T4).  It was also believed to reduce testosterone levels as a possible role in the anti-aggressive properties of the medication.  Studies at the time showed that in patients treated for aggression and closely followed, they had increased levels of luteinizing hormone but normal testosterone levels.  A significant theory at the time was that lithium worked by reducing T4 levels and this reduced beta-adrenoreceptor potentiation in mood disorders.  Lithium was also thought  to possibly work by the effect it had on the intracellular concentration of other ions like sodium, calcium, potassium, and magnesium in neurons. The 1980s was a decade when research interest on cell signalling was becoming more widespread after Sutherland's Nobel Prize for the discovery of cyclic AMP (cAMP).  Lithium was noted to inhibit adenylate cyclase the enzyme that produces cAMP.  Specific forms linked to beta-adrenoreceptors and prostaglandin-E1 were noted to be blocked leading to speculation that these mechanisms were related to mania.  

Another definitive source of drug mechanisms over the same era was The Biochemical Basis of Neuropharmacology.  My collection of these texts starts in 1984 with the fourth edition of that text.  There was a single paragraph on the action of lithium and its effect on catecholamines.  They used the term facilitated recapture mechanism (2) suggesting that the overall block  of stimulus related norepinephrine (NE) release may be due to facilitated uptake of NE.  They also point out the difference in acute and chronic effects with supersensitive NE responses with chronic administration.  By the fifth edition of this text (3), the speculative mechanisms had expanded to include inhibiting inositol-1-phosphatase in the phosphoinositide pathway (p. 114), the same NE mechanism as the previous edition (p. 306), and a new observation that lithium facilitates tryptophan uptake initially but with chronic administration tryptophan production normalizes despite increased uptake due to decreased enzymatic conversion to serotonin (5HT).  Shifting the balance between synthesis and uptake was suggested as a more stable mechanism.  By the seventh edition, lithium was back to being mentioned on single page  as part of the larger discussion of deficits in the catecholamine hypothesis of mood disorders - a theme the authors started in the fourth edition.  By the eighth and final version of this text there was no mention of lithium at all.  Two of the authors were involved in a successive text called Introduction to Neuropsychopharmacology (5).  That text describes lithium as "one of the major achievements of psychopharmacology of the past 50 years (p. 321).  The authors acknowledge that the mechanism of action remained unclear but the theories included inhibition of inositol monophosphatase, inhibition of glycogen synthase kinase-β, and modulating g protein function (p. 321).

Another excellent source of the evolution of lithium theory was the American College of Neuropsychopharmacology's (ACNP) Generation of Progress series.  The series has been discontinued.  I have the third to the fifth editions and the most substantial section on lithium action was in the Fifth Generation of Progress (6).  This chapter begins with an overview of the time course of mood stabilizer action and how the focus had changed over the previous 20 years from changes in neurotransmitter release and regulation to changes in cell signalling and morphological changes consistent with "altered signalling in critical regions of the brain."  The chapter is an overview of the complex effects of lithium on ion transport, neurotransmitter release, signal transduction, circadian rhythm, gene expression, and neuroplasticity.  The data showing that lithium and in some cases valproate and carbamazepine can regulate gene expression via transcription factors is reviewed.  Some of the changes produced a neuroprotective effect against a number of factors and at about that time neuroprotection was considered a potential positive effect form both mood stabilizer and antidepressants.  It was very interesting to reread the section on neuroplasticity.  Lithium was known to be an inhibitor of glycogen synthase kinase-3 beta (GSK-3β).  This molecule is a component of the wnt signalling pathway (see diagram).  This inhibition results in reduced phosphorylation of tau protein and the overall effect of  increased microtubule assembly.  Phosphorylation of MAP-1β is also inhibited by lithium and this results in increased axonal spreading and increased growth cone area and perimeter.  Long term down regulation of protein kinase C (PKC) substrate myrisolated alanine-rich c-kinase substrate (MARCKS) via phosphoinositide signalling was also shown to MARCKS expression is high in developmentally important structures like neuronal growth cones necessary for brain development.  It is also high in limbic structures in the human brain that retain the potential for plasticity - like learning and memory.  The authors conclude that section by pointing out that by its action on PI/PKC and GSK-3β signalling cascades, lithium "may alter presynaptic and post-synaptic structure to stabilize aberrant neuronal activity in critical areas of the brain involved in the regulation of mood."  In the space of just a few years, lithium was suddenly implicated in neuroplasticity and neuroprotection.  Maybe the Decade of the Brain did produce some benefits?  

That brings me to the latest piece of the puzzle.  A paper from Molecular Psychiatry (7) this October further examines the role of these signalling systems and how everything comes together.  The authors propose that one common biochemical pathway that may confer susceptibility to psychiatric disorders is the Wnt/ β-catenin pathway.  This is a pathway that is critical in all multicellular organisms for cell differentiation, growth, proliferation and morphology across a number of organ systems.  At least part of the pathway has a direct influence on the cytoskeleton.  It has been implicated in human diseases especially tumors and the metabolism of tumors.  The pathway was discovered about 34 years ago.  The  authors also looked at DIX domain containing-1 (DIXDC1) as a cytoplasmic transducer of the Wnt/ β-catenin pathway.  DIXDC1 interacts with disrupted in schizophrenia-1 (DISC-1) gene that has been implicated in the genetics of schizophrenia, bipolar disorder, and autism spectrum disorder.  DIXDC1 also has a restricted distribution in the nervous system depending on developmental stages.

Like most modern papers this article has an intense experimental section.  The authors prepared a DIXDC1 knockout mouse model and looked at several experimental manipulations.  They used several behavioral pharmacology approaches to model anxiety, depression, and social interaction among the mice.  On these models the Dixdc1KO (knock out) mice showed increased depression, increased anxiety, and less socialization than the Dixdc1WT (wild type) mice.  These behavioral phenotypes correlated with histological changes and the Dixdc1KO mice had reduced spine density and an increased number of filopodial or immature spines on pyramidal cell dendrites.  The authors confirmed that these reduced spine neurons functioned in an electrophysiologically expected manner.  They analyzed the reduced spines in the Dixdc1KO mutants and found that there was a decreased density of glutamatergic synapses along the dendrites of pyramidal neurons.  In order to determine if the Dixdc1KO Wnt/ β-catenin pathway would be impaired by the loss of cytoplasmic signal transduction proteins.  They found that treating the KO and WT neurons with and activator (Wnt3a) - the  level of β-catenin rose as expected in the WT neurons.  Wnt3a also failed to effect spine maturity or glutamatergic synapse density on the KO type neurons.

Most importantly for psychiatrists, the authors hypothesized that lithium would correct both the behavioral phenotype and structural defects in the Dixdc1KO type mice by inhibition of GSK3.  Injection of lithium or the specific GSK inhibitor GSK3i corrected the behavioral phenotypes and spine density, spine morphology, and glutamatergic synapse density in the pyramidal neurons of Dixdc1KO mice.                        

In a separate experiment the authors looked at a large database of patients with psychiatric disorders.  The first database contained 6000 cases of autism spectrum disorder (ASD) and 7000 controls.  The ASD cases had a greater number of sequence disrupting single-nucleotide variants (SNVs) that were judged to be likely to disrupt DIXDC1 function.  They showed the same pattern in patients with bipolar disorder (BD) and schizophrenia (Scz) versus controls.  In the end they had 4 patient data sets totaling 9000 cases (versus 11000 controls) with significantly more rare sequence disrupting SNVs.

The authors also used a cell based Wnt/ β-catenin signalling assay (compared to WT) to test specific missense SNVs from both psychiatric patients (BD, Scz) and ASD patients.  They found that rare missense SNV from ASD patients either increased or decreased Wnt/ β-catenin pathway activation.  Rare missense SNVs from psychiatric patients did not rescue spine density and synaptic deficits but the WT did.  A number of Wnt/ β-catenin pathway hyperactivating SNVs cased the expected decreased spine density, decreased glutamatergic synapse density and increased immature spine density.

The authors conclude that there may be other mechanisms in play that they could have missed.  They cite a downstream mechanism that is independent of the Wnt/ β-catenin pathway that leads to the structural changes they monitored in this study.  There are also different isoforms of DIXDC1 - some more active than others.  They do a great job of summarizing 20 years of research in the following lines:

"Several different biochemical mechanisms have been proposed to underlie the anxiolytic, antidepressant and mood stabilizing properties of lithium, a drug whose systemic use in modern psychiatry began in the first half of the last century.  Lithium's best validated mechanisms of action are inhibitory on IMP and INPP1, central phosphatases in the phosphoinositide pathway and on GSK3, the central kinase in the Wnt/ β-catenin pathway and AKT pathways."  (p. 8).  

 The story of lithium is similar to a lot of stories in biomedicine.  Research on lithium reflects a lot of popular theories of the day rather than any particular unique theory by one scientist.  That says a lot about the difference between physical sciences and biological sciences.  The technique of applying the most popular theories and lab techniques at the time is still common in medicine and neuroscience.  Like most neuroscience there needs to be further testing, replication, and debate about this mechanism but it does seem to be a lot clearer now than at any time in the past.  If the mechanism does check out there may be more than the few applications that currently involve lithium.  A lithium like effect from safer medications is potentially a very interesting one.  Applications may be as diverse as treating addiction - where glutamatergic innervation is thought to be an important component of top down control from the frontal cortex to neurodegenerative disorders and neuroprotection of synaptic complexity.

George Dawson, MD, DFAPA



References:

1:  James W. Jefferson, John H. Griest, Deborah L. Ackerman.  Lithium Encyclopedia for Clinical Practice.  American Psychiatric Press,  Washington, DC; 1983.

2:  Jack R. Cooper, Floyd E. Bloom, Robert H. Roth.  The Biochemical Basis of Neuropharmacology.  4th ed. Oxford, England: Oxford University Press, 1982: 214.

3:  Jack R. Cooper, Floyd E. Bloom, Robert H. Roth.  The Biochemical Basis of Neuropharmacology. 5th ed.  Oxford, England: Oxford University Press, 1985: 115, 306, 319.

4:  Jack R. Cooper, Floyd E. Bloom, Robert H. Roth.  The Biochemical Basis of Neuropharmacology.  7th ed. Oxford, England: Oxford University Press, 1996: 490.

5:  Leslie L. Iverson, Susan D. Iverson, Floyd E. Bloom, Robert H. Roth.  Introduction to Neuropsychopharamcology.  New York, New York: Oxford University Press, 2009: 321-322.

6:  Robert H. Lenox, Alan Frazer.  Mechanism of action of antidepressants and mood stabilizers. In:  Davis KL, Charney D, Coyle JT, Nemeroff C, eds.  Neuropsychopharmacology: The Fifth Generation of Progress. Philadelphia, Pennsylvania: Lippincott, Williams, and Wilkins, 2002: 1139-1163.

7:   Martin PM, Stanley RE, Ross AP, Freitas AE, Moyer CE, Brumback AC, Iafrati J, Stapornwongkul KS, Dominguez S, Kivimäe S, Mulligan KA, Pirooznia M, McCombie WR, Potash JB, Zandi PP, Purcell SM, Sanders SJ, Zuo Y, Sohal VS, Cheyette BN.  DIXDC1 contributes to psychiatric susceptibility by regulating dendritic spine and glutamatergic synapse density via GSK3 and Wnt/β-catenin signaling.  Mol Psychiatry. 2016 Oct 18. doi: 10.1038/mp.2016.184. [Epub ahead of print] PubMed PMID: 27752079.

8:  Saito-Diaz K, Chen TW, Wang X, Thorne CA, Wallace HA, Page-McCaw A, Lee E. The way Wnt works: components and mechanism. Growth Factors. 2013 Feb;31(1):1-31. doi: 10.3109/08977194.2012.752737. Review. PubMed PMID: 23256519

Attribution:

Wnt signalling pathway is from VisiScience and their ScienceSlides 2016 slide set.

Say What You Mean.........

I read an elegant editorial piece during breakfast this morning.  It was in the regular section in JAMA called "A Piece Of My Mind".  Amanda Fantrey, MD writes about some of the insights she developed as a family member in an ICU setting after her brother was involved in a motor vehicle accident and sustained a traumatic brain injury and coma.  She describes the pull on doctors to make statements that offer hope and frequently diverge from the realistic medical appraisal of the situation.  She describes this as "the seismic gap between what was said by staff (both physicians and nurses) and what was heard by family."  A common example is the staff remembering the one patient with a miraculous recovery and bringing that up in discussions with the family as a way to give them hope.  Dr. Fantrey points out the origins of this behavior as wanting to reassure a traumatized and grieving family.  She gives a clear example of how this plays out in a discussion between the neurosurgical team and her parents.  What seems like a grim prognosis is suddenly being moderated by qualifiers. With enough modification the initial grim prognosis becomes the expectation of recovery.  She also points out that another level this is self preservation - a bias toward recalling the miracle cases and saves.  That without it practicing medicine and surgery is just too grim to contemplate.  This is an excellent essay that I would recommend to any medical student or resident as an example of the power of affective communication, language, and interpersonal dynamics.

The interactions that Dr. Fantrey describes on medicine are common.  I think they form the basis for a number of commonly observed phenomenon.  Psychiatric practice is no exception.  The first thing that came to mind is the promise of the miracle drug that will take away all of your problems.  Many psychiatrists witness first hand patients who explicitly ask them for this kind of medication.  Many people become addicted to opioids because at the outset - it seems like these medications have the properties of an ideal medication.  There has been abundant criticism that new medications are oversold both by advertising and the way that advertising affects the pharmacology literature.  I am much less certain of that as there is more evidence accumulating that the pricing power of the companies themselves is the single largest factor driving much higher pharmaceutical prices and profits in the US.  There is the inescapable sense of hope being conveyed through both direct-to-consumer advertising and and the novelty of a new drug.  Although it has not been adequately tested, that new drug is a form of hope in a pill.  The interested people are all hoping for better therapeutic effects even in spite of the rapid delivery of a list of serious side effects "including death" at the very end of the commercial.

It also brought to mind some of the serious discussions that psychiatrists have with patients and how the biases might be a little different.  The most obvious one is lithium.  Lithium is one of the best medications in terms of therapeutic effects that psychiatrists prescribe.  The attitude of other physicians seems to be: "We will let them prescribe that medication almost exclusively" or "You psychiatrists sure do prescribe a lot of toxic medications."  Treating people with the most severe forms of mental illness almost exclusively for 30 years has caused me to witness many miracles of lithium therapy.  The commonest was the depressed bipolar patient not able to eat, barely taking in fluids, and certainly not able to function outside of a hospital setting.  After starting lithium, many of of these folks recover enough function within a week to be up in the daytime, eating and starting to care for themselves.  For me the miracle of lithium has been on the depressed side.  People who have failed antidepressants and whatever anticonvulsant is en vogue for bipolar disorder.

There is no other medication prescribed by psychiatrists that invokes fantasies and expectations more to patients than lithium.  Their expectations are generally very bad as in:  "That is some serious shit - dude..  Isn't that the medicine in that song......"  I have to remind people that the band was Nirvana and yes I am old enough to have watched them perform the song Lithium live on Saturday Night Live.  I have to explain calmly that it is a salt and that this makes it a unique kind of medicine with fairly unique precautions but that is can be safely taken.  I do point out that is if they end up taking it for decades or if they have repeated episodes of lithium toxicity - it can cause renal failure in some and the need for dialysis and renal transplantation.  I know this because of my experience with end stage renal disease that was attributed to lithium by my Renal Medicine consultants and the protracted course of dialysis, in some cases delirium, and ultimately renal transplantation.  I try to outline all of that, but it is hard to imagine how much information is getting through.  Like Dr. Fantrey's ICU experiences, nobody is more acutely aware of needing to provide hope than a psychiatrist talking directly to a depressed bipolar patient.  We are simultaneously assessing suicide risk - even in inpatient settings.  Acute care psychiatrists know that this is our job.  We have to keep this person alive so that they can recover.

I have to cautiously present the information on lithium as part of the informed consent discussion, but at some point I also started to include a line about lithium being a "potentially life-changing medication."  I explain that the person may experience mood stability like they have never had on the endless series of antidepressants, atypical antipsychotics, benzodiazepines, various anticonvulsants and the drift toward an inaccurate schizoaffective disorder diagnosis that they have been experiencing for years or decades.  I am always concerned about whether they hear the word potentially in my description.   I provide them with a detailed handout on lithium and encourage them to do whatever research they would like to do on the medication and I will answer any further questions.  Is this just another example of hope enacted in the countertransference, me trying to convey it to a desperate patient?  It is hard to imagine that patients who view lithium as a toxin at the outset could have unrealistic expectations about the drug.  Am I coloring their expectations by my description of the drug?  Would it be unfair to not include that information about potentially changing their life?

I think there are problems with all complex informed consent discussions.  These discussions can't be devoid of emotional content.  Like the surgical patients, some people will do better and some will do worse.  It is difficult to determine that ahead of time.  Every patient I see needs to benefit from my experience treating other patients.  And with lithium it is very good.  


George Dawson, MD, DFAPA


References:

Fantry A. Say What You Mean, Mean What You Say. JAMA. 2016;315(13):1337-1338. doi:10.1001/jama.2015.18910.






 

University of Wisconsin 2nd Annual Update

I was in Madison Wisconsin for the Second Annual University of Wisconsin Clinical Update.  I reviewed the first conference last year.  For anyone unfamiliar with the conference it started last year as a replacement for the long running conference run by John Greist, MD and James “Jeff” Jefferson, MD.  They were acknowledged again this year for their contributions to psychiatric education.   This is a very good conference because it builds on that tradition.  The actual venue is the Monona Terrace Convention Center on the shore of Lake Monona.  It is an excellent modern facility with only one drawback - they charge for high speed wireless access.  I talked with many psychiatrists there who had attended the previous conferences for a long time.  They bring in speakers who are some of the top experts in their fields for in depth presentations and there is also a strong department at Wisconsin headed by Ned Kalin, MD.  The conference wraps up in in a day and a half and that seems like a very good length for working psychiatrists.  Combine that with very accessible speakers and an excellent course syllabus and it has what I consider to be the elements of a good educational experience.  The other bonus is that I have never really seen an unbalanced presentation at this conference.  The overarching message is that there are a number of interventions, that treatment is successful, and that there is a scientific basis for what psychiatrists do.

I thought I would make a few comments on day 1 and then move on to day 2.

The first lecture was given by Maria A. Oquendo, MD on the Neurobiology, Assessment, and Treatment of Suicidal Behavior.  Aleman and Denys have called for the investigation of suicide as a special problem apart from any particular diagnosis.  She began with a review of the epidemiology of suicide, including the fact that 90-95% of suicides have an psychiatric disorder.  She also discussed the converse of that statement - the vast majority of patients with psychiatric disorders never attempt suicide.  That statement is usually not discussed.  It is a parallel argument to violence and aggression in psychiatric disorders.  It has implications for any care based on dangerousness (threat of aggression or suicide).  She presented an interesting stress diathesis model of suicidal behavior that takes into account clinical features (impulsivity, cognitive inflexibility,  substance use,  family history, poor social support) and neurobiological features (low serotonin, decreased noradrenergic (NA) neurotransmission, inflammatory markers).  Her model links norepinephrine neurotransmission with pessimism.   She cited evidence that included a slide of CRH innervation of NA neurons and behavioral models that lead to NA depletion in animals.   She reviewed some of the evidence of inflammatory signaling related to childhood adversity, the mechanism of interferon-alpha induced depression and markers of inflammation in suicide attempters versus controls (increased interleukin- 6 (IL-6), tumor necrosis factor - alpha (TNF-alpha), elevated microglial cells, increased IL-4 in women, and increased IL-13 in men.  The tentative conclusion is that suicide occurs in the context of a stress response or at least it appears to have the same neurobiology of a stress response.   She concluded with a discussion of public health approaches to preventing suicide.  She had no specific recommendations for how psychiatry fits into that response apart from presenting data that increased antidepressant prescriptions led to decreased suicide rates in Sweden, Hungary, Japan, and Slovenia.   She also discussed specific psychotherapeutic interventions for suicide by name and presented a study of cognitive behavioral therapy that led to a 50% reduction in suicide attempts.   Dr. Oquendo also provided an excellent contrast in how the results of observational studies, meta-analyses, and double blind placebo controlled studies can differ and what biases may be in effect.  In the case of lithium preventing suicidal behavior, most clinicians are aware of the fact that only lithium and clozapine are consider medications that prevent suicide.  In the case of lithium, it turns out that data is from observational studies and meta-analyses but not double blind placebo controlled trials.  The two double blind studies do not suggest that lithium is more effective in preventing suicides than other agents.  She suggested one bias may be a tendency of clinicians to use lithium in people who can use it more safely and that led to fewer suicide attempts.          

I found the presentation on suicide and suicide assessment very interesting.  It is such a broad topic that a single lecture has to pick a focus.  The presentations on suicide that I have seen tend to focus on trying to figure out which people attempt suicide and interventions in those populations.    People with psychosis and suicidal ideation – a common clinical scenario for psychiatrists are generally left out.  It would definitely complicate the presentation at a couple of levels.  There is the issue of what happens to the usual risk factor analysis, especially in the case of subtle forms of psychosis.  Factors that are typically seen as reliable (deterrents to suicide, prevention plans) can be thrown out in that situation since the patient has had a marked change in their conscious state.  That is true whether or not the patient is clinically interviewed or given a structured interview like the CCRS.   In the case of psychotic individuals paranoia is also a risk factor for suicidal behavior.  The paranoia is focused on a particular situation where the individual believes that he or she will be tortured or killed by someone.  They develop a plan to kill themselves rapidly using a highly lethal method before that can happen.   A common scenario is to have a knife or handgun on the nightstand just in case it becomes necessary.  In both of these treatment situations, the preferred course of treatment is to address both the depression and psychosis at the same time.   Past studies of these populations also suggest very high levels of hypothlamic-pituitary-adrenal (HPA) axis activation, consistent with Dr. Quendo's model.

Roger McIntyre, MD followed with Practical Considerations in the Successful Treatment of Bipolar Depression.  There seems to be fairly widespread confusion about the diagnosis of bipolar disorder.  I think it is common for consulting and subspecialty psychiatrists to reverse the diagnosis of bipolar disorder more often than they make new diagnosis.  Dr. McIntyre made that point but said that misdiagnosis is still a problem even in an era of overdiagnosis.   He took the assessment up a notch to discuss the utility and limitations of the diagnostic issues of bipolar qualifiers in DSM-5 ( mixed features, anxious distress) and what they imply for diagnosis and treatment.  He also emphasized the need for time to do an assessment.  He appreciates the fact that primary care physicians may have as little as 6 minutes to make a mood disorder diagnosis but said that even in his specialty clinic he may not know the diagnosis of 25% of the patient after doing a lengthy assessment.  He made this point to illustrate that in many patients a single cross sectional view of symptoms in a clinic appointment is insufficient to make the correct diagnosis.

He presented an excellent graphic showing the DSM-5 continuum from manic to manic with mixed features to depressed with mixed features to depressed.  He also spent a fair amount of time discussing the treatment of comorbid anxiety as a significant morbidity in bipolar disorder.  He presented interesting data on how comorbid medical and psychiatric conditions in bipolar disorder were the rule rather than the exceptions.   His main focus was on metabolic syndrome, obesity, and migraine headaches.  He presented very good graphics on mechanisms associated with these comorbidities.  He made the point that the metabolic abnormalities (much like studies done in patient with schizophrenia who had never been treated with medications) were associated with a number of social, metabolic, and environmental factors.  He suggested that the obesity/major depression and obesity/bipolar disorder phenotypes carried specific risks including poor cognitive performance, anxiety symptoms, and in the case of depression a possible higher suicide risk.   He cited estimates of metabolic syndrome ranging form 20-66% in populations with bipolar disorder compared to a general population estimate of 23.7% from the NHANES III study.  He presented interesting data on the correlation between cognitive impairment in obese and overweight bipolar patients that can be demonstrated in first episode manic patients (obese versus non-obese).  At the molecular level it has been demonstrated that there is a gradient of inflammatory markers between obese and non obese bipolar patients.   He has a published paper that looks at the relationship between treatment response in depression and body weight.  Although he did not speculate on an exact mechanism he suggested there were altered brain systems involved in cognition in many of these patients.

The section of Dr. MacIntyre's lecture included an interesting graphic that had all FDA and EMA (European Medicines Agency) approved medications for bipolar-manic, bipolar depressed, and maintenance therapy.  Both agencies have approved quetiapine for bipolar and only the FDA has approved lurasidone and olanzapine-fluoxetine combination (OFC).  The number of medications not approved in all columns is about the same (4 for EMA and 3 for FDA).  He presented number needed to treat (NNT) and number needed to harm (NNH) analyses for OFC, quetiapine, and lurasidone and in that analysis lurasidone looked like the superior medication but that analysis is for specific side effects.  The NNT was nearly identical for all medications.  In terms of overall treatment he was in general agreement with the Florida Medicaid Drug Therapy management Algorithm.   One of the very interesting points he made during his presentation was that treating and preventing recurrent manic  episodes may reduce risk for Alzheimer's dementia but that is potentially confounded by the effect of lithium on GSK-3-induced tau phosphorylation.         

Lithium Pearls (From several lectures)

1.  The claim that lithium is one of two medications that can prevent suicide is based on observational studies and meta-analyses.  There have been two double blind studies looking at this issue and they have both been negative.

2.  Experts continue to use lithium and consider it to be one of the major treatments for bipolar disorder.  Lithium may provide more benefit to manic prone patients with long periods of stability and a positive family history.

3.  Once a day dosing was recommended.

4.  Lithium can be used in pregnancy given several specific precautions and informed consent issues; including precautions are the time of delivery to prevent elevated lithium levels in the newborn.

5.  Lithium may decrease the risk of Alzheimer’s Disease and minimal cognitive impairment.

   
After afternoon breakout sessions on various topics, the final presentation was by Ned Kalin, MD on the Neurobiology of Depression.  As a point of disclosure I know Dr. Kalin and was his first fellow at the University of Wisconsin back in 1984 and I completed my residency there.  He is a model of the clinical researcher who has seen patients his entire career and also been involved in basic science research.  There were several other department members at Wisconsin engaged in the same balance of clinical and scientific activities.   I learned that he was also President Elect of the Society of Biological Psychiatry.  The UW has always been active in primate research and Dr. Kalin discussed some important ethical and scientific issues about basic science research in non-human primates including the reason for primate research and the changes in standards and research settings over the years.  He has broadened his research over the years to include how depression and anxiety start in childhood and adolescence.   He posted an interesting graphic on deaths worldwide due to violence that suggested suicide was the top cause, followed by homicide and then warfare.  It was based on World Health Organization (WHO) data.  He showed experimental data on conscious regulation of the amygdala.  These interesting studies show that activity in the amygdala can be modulated by cognitive activity that either enhances of decreases the response to the feared stimulus.  The ventromedial prefrontal cortex (vmPFC) and orbitofrontal cortex (OFC) are critical associated areas with activity correlating inversely with activity in the amygdala (high vmPFC and OFC activity correlate with low activity in the amygdala).   Preliminary data suggests that depressed patients fail to suppress activity in the amygdala with vmPFC and OFC activity.  A similar change occurs in the ventral striatum when depressed individuals attempt to enhance their positive affect over the course of an imaging session.  Controls show a significant increase in left nucleus accumbens activity (LNAcc).

Dr. Kalin reviewed the genetics and environmental factors in depression using a graphic that cited 3 of Kendler's papers.  He reviewed the progression of hypotheses ranging from monoamine depletion to altered serotonin neurotransmission to serotonin alteration hypothesis to  stress diathesis to neurotoxins to inflammatory/cytokine theories.  One of the possibilities he discussed was a theory that at least some developmentally based depressions are based on frontal cortical-amygdala substrates that result in increased activity in the amygdala and associated neuroplasticity mechanisms that also lead to increased vulnerability.   Cognitive therapy for depression may strengthen the ability of the frontal cortex to regulate the amygdala.  One of his areas of intensive investigation has bee the HPA axis and its effect in depression.  He reviewed the important roles of CRF both as an endocrine modulator and a neurotransmitter.   He used a Vonnegut quote from Breakfast of Champions as a quick review of HPA axis physiology.  For anyone who had read the book (and forgotten some physiology) it was an interesting reference.   In the last quarter of the lecture he reviewed the issue of stress in separated infants, maternal stress, and adults in human and non-human primates.  The focus was primarily on neuroanatomy, neuropathology, neuroendocrinology and possible treatments that target these systems.  Earlier in his discussion he also posted a graphic on translational neuroscience and how neuroscience findings need to be able to correlate at the clinical level.  A detailed discussion of that approach is available in this article that is available online at no cost.              

The first day in Madison went as well as expected.  Lectures with very high quality content by researcher-clinicians who actually see patients and investigate clinically relevant topics.  Psychiatry taught, researched, thought about, and practiced the way it should be.


George Dawson, MD, DFAPA



1: Oquendo MA, Galfalvy HC, Currier D, Grunebaum MF, Sher L, Sullivan GM, Burke AK, Harkavy-Friedman J, Sublette ME, Parsey RV, Mann JJ. Treatment of suicide attempters with bipolar disorder: a randomized clinical trial comparing lithium and valproate in the prevention of suicidal behavior. Am J Psychiatry. 2011 Oct;168(10):1050-6. doi: 10.1176/appi.ajp.2011.11010163. Epub 2011 Jul 18. Erratum in: Am J Psychiatry. 2012 Feb;169(2):223. PubMed PMID: 21768611

2: Lauterbach E, Felber W, Müller-Oerlinghausen B, Ahrens B, Bronisch T, Meyer T, Kilb B, Lewitzka U, Hawellek B, Quante A, Richter K, Broocks A, Hohagen F. Adjunctive lithium treatment in the prevention of suicidal behaviour in depressive disorders: a randomised, placebo-controlled, 1-year trial. Acta Psychiatr Scand. 2008 Dec;118(6):469-79. doi: 10.1111/j.1600-0447.2008.01266.x.

3: Fox AS, Kalin NH. A Translational Neuroscience Approach to Understanding the Development of Social Anxiety Disorder and Its Pathophysiology. Am J Psychiatry. 2014 Aug 26. doi: 10.1176/appi.ajp.2014.14040449. [Epub ahead of print] PubMed PMID: 25157566.

4: McIntyre RS, Rosenbluth M, Ramasubbu R, Bond DJ, Taylor VH, Beaulieu S, Schaffer A; Canadian Network for Mood and Anxiety Treatments (CANMAT) Task Force. Managing medical and psychiatric comorbidity in individuals with major depressive disorder and bipolar disorder. Ann Clin Psychiatry. 2012 May;24(2):163-9. Review. PubMed PMID: 22563572.


Supplementary 1: I thought it was very interesting that we are still talking about lithium as a very effective medication for psychiatric disorders int he same city that hosted the Lithium Information Center cofounded by Greist and Jefferson and the same location where the Lithium Encyclopedia for Clinical Practice was published.