Sunday, January 21, 2018

My Opinion on Community Mental Health From 1989....



A friend of mine who also worked with me as an RN on an acute care psychiatric unit sent me this newspaper clip from 1989.  It is from the St. Paul Pioneer Press.  At that time I had just started working on an acute care inpatient unit at St. Paul-Ramsey Medical Center (SPRMC) after working in a community mental health center (CMHC) for three years.  The CMHC was in northern Wisconsin and SPRMC is in St. Paul, Minnesota.  In this brief letter to the editor, I was listing the style points between both systems.  Wisconsin was known to be an innovator in community mental health essentially inventing active outreach, providing meaningful crisis intervention services, and active case management with a goal of keeping people with severe mental illnesses in their own apartments in the community and out of hospitals.  Anyone with any experience at all realizes that this is the best approach to the problem.  We did not worry about it at the time, but it also kept people out of jail.  We had working relationships with law enforcement and would often see people in jail and facilitate their treatment there and transition back to the community.

As the medical director of a CMHC in Wisconsin in those days, I had a team meeting with case mangers and nursing staff every morning.  We discussed crises and treatment plans for the 100 to 110 individuals under our care.  After that meeting everyone (except me) was driving off to meet our patients in the community.  We had an exemplary record of helping these folks stay out of the hospital and our case managers would go to the hospital and help get them discharged if they were at baseline.  We knew the resources, landlords, relatives, doctors, and local crisis housing.  We worked within a system that had a single-minded focus of supporting people in the community and at the administrative level we had state support mandated that the "money follows the client".  That did involve an incredible amount of paper work on the part of our case managers and needing to deal with a county bureaucrat but there were clear significant advantages over other systems.

Flashing forward 30 years has there been much progress?  I can say with certainly there has been absolutely no progress on the Minnesota side.  They have funded some assertive community treatment (ACT) teams but there is still a rationing mentality.  I heard the rationing mentality recently restated by the current head of the state hospital system.  Minnesota currently has a large steady state population of chronically mentally ill patients circulating through emergency departments, available beds, jails, and homelessness.  There is limited bed availability to the point that outpatient psychiatrists have to send their patients to the emergency department (ED) rather than referring them directly to affiliated hospital because they know there are no beds. That is also true for patients who need electroconvulsive therapy.  The constant stream of people to the ED creates a backlog there and getting patients out occurs only if they are held long enough for an inpatient bed to open, discharged untreated, or transferred to another hospital often several counties away.  In the meantime, the state hospital system has been reduced.

In a November meeting of the Minnesota Psychiatric Society (MPS), Kylee Ann Stevens, MD the Executive Director Direct Care and Treatment of the state hospital system provided some numbers for mental illness treatment but not addiction resources.  Those numbers are summarized in the graphic below.      


It is apparent by inspection that there has been a massive reduction is state hospital beds.  Just over the course of my career they have dropped by over 1,000%.  The bed situation is compounded by a "48 hour rule" enacted in 2014 that states that all patients with a question of mental competency in jails or correctional institutes must be admitted to a state facility within 48 hours.  That gives county Sheriffs preferred access to state hospital beds over treating psychiatrists.  Rather than look at recommended hospital beds per population the state does not plan to try to increase the beds.  A quote from the  National Association of State Mental Health Program Directors (NASMHPD) that "Building more inpatient bed capacity to meet demand is unsustainable" provided the rationale.  The conflict of interest there is obvious.  State Directors are basically accountable to politicians and bureaucrats who want to ration state supported health care especially to those with the least vocal advocacy. At one point in Minnesota over 11,000 beds were sustainable. The only thing different today is politics.

There is also a chronic unanswered question that has been hanging in the air for the last 20 years.  Did Minnesota intend to just shut down the state hospital system entirely? Certainly the trajectory of bed closures was on track to do that.  In the MPS meeting we never learned what the absolute minimum number of beds was.  In talking with doctors and nurses who worked in that system they certainly thought that was the goal.  The current minimalist system may be in place by default rather than design - the end product of a failed attempt to close down all of the state hospital beds.

So Minnesota continues to flounder.  What about Wisconsin?  I don't think that their inpatient bed capacity is much better but I don't have the exact number.  The community mental health movement is still alive and well but I am aware of no significant innovation.  The Wisconsin Mental Health Statutes appear to have expanded significantly and law enforcement seems to have assumed more of a gatekeeper role in emergency treatment.  I can't comment on whether the Wisconsin system is more cost effective and patient centered than Minnesota but I invite clinicians to comment on that.

Relative to the initial news clip - progress in general in the treatment of psychiatric disorders is not a word that can be used.  Politicians run these systems and not physicians.  As long as that is true we can depend on no progress.

George Dawson, MD, DFAPA  
News Flash From the StarTribune - Psychiatric Patients Have "Nowhere To Go"

Minnesota's Mental Health Crisis - The Logical Conclusion of 30 years of Rationing

Running the numbers Minnesota has 3.2 state hospital beds for 100,000 people.



Monday, January 15, 2018

A Short (11 minute) Film About Alcoholism - Breakfast Wine






"In Ireland, they say it takes just 3 alcoholics to keep a small bar running in a country town....."



I ran into this film last week and was impressed enough to write this post about it.  It is an award winning short film about four people in a pub in rural Ireland and events that transpired on a certain day.  Given the availability and brevity of the film, I encourage anyone interested to view the video before reading this post.

You can go to any number of Saturday Night Live skits and see alcoholics ridiculed.  This film takes the problem more seriously. What you see will depend on your experience observing and interacting with people who have an alcohol problem.

To set the scene, the film begins with the quote posted at the top of this page.  We see two middle-aged men standing outside a pub waiting for it to open.  The owner shows up.  They all enter and the two men who were waiting commence drinking pints of Guinness.  Over the duration of the time lapse in the film they each drink 6 pints of Guinness - the first two in what seems fairly rapid succession.

After they put down about two pints a young woman enters, asks them about the availability of wine.  After getting their recommendations she proceeds to drink the first glass rapidly. Over the time lapsed in the film she drinks a total of 4-187.5 ml bottles. The pub owner and the two men in the bar seem impressed with her ability to drink, but they are also impressed with her ability as a ranconteur.  She tells a fable about getting rid of all motor transport and lining people up against the wall and shooting them.  She moves on to describe severe physical abuse by her husband and shows lacerations on her wrists where she was tied up on the garage floor.  She tells them what her husband was saying to her when he became abusive and does not miss a beat.  She sarcastically dismisses her rant by saying "I should have seen it coming."  At that point she says good bye and the pub owner tells her what the opening time for the pub is every day.  She thanks him for the information and walks out.  The men are clearly impressed with her and one of them longingly touches the stool where she was  sitting.

At the level of entertainment, I can see why this is an award winning short.  The writing and acting are good.  The woman in the scene, actress Ruth Bradley is a compelling screen presence.  She plays this  role perfectly. It is a plausible scene from any bar - Irish or American. From the standpoint of an addiction psychiatrist - what is wrong with this picture?

The alcohol consumed per unit time is a red flag.  The CDC defines binge drinking as probably occurring if a woman consumes 4 or more drinks or a man consumes 5 or more in 2 hours.  The time span of this film may be subject to debate but I counted 6 pints of Guinness per man or 9.6 standard drinks and 750 ml wine (4 - 187.5 ml bottles) or 5 standard drinks for the woman.  It is clear from the depiction by the actors that they are drinking these beverages at times like water.  In bars or pubs bad things tend to happen when the patrons are binge drinking. Binge drinking alone whether it is associated with a diagnosis of alcohol use problems has associated mortality and morbidity per the CDC site.

 There is a high tolerance for unusual behavior in the pub.  One of the men leaves and his behavior is discussed among the remaining people.  In another scene marking the sixth pint he becomes irate with his associate and that behavior is translated as an acknowledgement that he does want another pint.  The woman had two discrete rants about motor vehicles and the violence she has sustained by her husband and immediately resumes a normal even joking manner.  The men are intensely interested in this woman, she breaks up their routine, is attractive to them and is charismatic.  Their response to her description of the violence she has sustained and even the presentation of her wrist lacerations is definitely muted. No one is interested in the violence or her newly acquired wounds, everyone is interested in moving on as soon as possible.

The dynamic that jumps out at me whether I am listening to heavy drinkers talk about relationships or observing them first hand in bars is grandiosity.  Grandiosity can be a feature of mood disorders or narcissism.  One theory of grandiosity in narcissism is that there is an inadequate mental representation of affirming objects representing attributes or real relationships in the environment.  If people with those attributes are absent or the people present have an inadequate positive affiliation with the person in question they can form their own representations.  That leads to grandiosity and narcissism  as an amplification of a deficient process with more realistic balances.  In alcoholism this can occur as a reaction to the hopelessness of the addiction and its sequelae.  As an example, a bar full of middle-aged men with alcoholic liver disease betting on who is going to die first.  Sometimes it occurs on a larger scale - the family that supports their father's grandiose statements about drinking himself to death during a hospitalization for recurrent hepatic encephalopathy from alcoholic cirrhosis.  The person involved comes across as though they are indestructible - but at a deeper level they cannot reconcile the severity of their illness and their inability to stop drinking.

That is what I think the female character brings to this scene.  She is clearly in an abusive marriage that she fled earlier the same day that she comes into the pub.  She does not appear to be traumatized at all until she demonstrates the injuries and even then she is loudly mocking her husband and eventually herself: "I should have seen it coming!"  The men seem transfixed on this story - unable to challenge it or accept the reality of her status as an abused wife.

I saw one comment posted on the YouTube site from a person who watched this film on an airline flight.  He was left thinking about the lives of the people in the film and what happened to them.  That is natural enough and something I wondered when I encountered a heavily intoxicated young woman in Boston and tried to help her.  To me it is always a lesson in the dynamics of heavy alcohol use.  There is an element of intoxication involved, but there is more than that driving a lot of the interpersonal behaviors and what you see happening in a pub or bar.

Defensive behavior about the inability to stop can be part of that.                       

 

George Dawson, MD, DFAPA


Sunday, January 14, 2018

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.



Friday, January 5, 2018

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.