Summary

This commentary is an outline of recent advances concerning lithium research and treatment.

The poor management of lithium treatment by psychiatrists, about which I first commented over thirty years ago, has continued, largely unimproved (1-3).

The most effective driving force for change and improvement in patient care must come from ‘consumer pressure’, rather than from the medical profession, who continue to be unduly influenced and manipulated by pharmaceutical companies. Thus, out of patent and un-patentable drugs, like lithium, drop below the radar and get drowned by the avalanche of glitzy presentation of all that is new and expensive. Never has the expression ‘out of sight, out of mind’ been more apt.

The decrease in the use of lithium and the constant high use of antidepressants (and anti-psychotics) do not align with the science and evidence, or with recommendations from international guidelines.

Patients and their relatives and carers need to inform themselves from reliable sources, such as this, and make sure that their doctors do the right thing.

Lithium is an amazing and under-used drug — the only genuine ‘mood-stabiliser’, the only drug with solid evidence showing it greatly reduces long-term rates of hospitalisation and suicide — caveat:  it needs to be used carefully by an informed practitioner.

Lithium advances: Introduction

This information is not an over-view of all aspects of lithium; it is a comment on specific developments.

A recommended recent comprehensive reference book is: ‘The science and practice of lithium therapy’ (4).

The management of lithium treatment by psychiatrists, about which I commented some thirty years ago, remains poor, as has been repeatedly verified in the published research literature (1-3, 5), and in the stories of the patients who contact me via the web site.

There is much for doctors to catch up on and refresh their knowledge about.

Incidentally, for anyone who has noticed the continuing dribble of papers claiming, or denying, an association between lithium in the municipal water supply, and suicide, in-growing toenails etc. I suggest they read my commentaries about lithium in water and the diet (see L-hand menu), which explains what normal endogenous lithium blood levels are, and where lithium comes from. Needless to say, ‘endogenous’ serum levels are unbelievably low, and there is no conceivable connection between lithium in tap-water and human illness. 

Ethos and history

 ‘Progress, far from consisting in change, depends on retentiveness. ... Those who cannot remember the past are condemned to repeat it."  Santayana,The Life of Reason 1905 (6).

It is tedious to have to keep repeating this comment, but the poor use of lithium endures as a testimony to the poor pharmacological and medical knowledge of psychiatrists. It echoes the position with MAOIs.

As with so many aspects of patient care, an effective driving force for change comes from ‘consumer pressure’. From the demands of patients and their families, rather than from the medical profession.

Medical professionals seem incapable of weaning themselves off the teat of ‘big pharma’: they continue to be unduly influenced and manipulated by pharmaceutical companies; thus, out of patent and un-patentable drugs drop below the radar and just get snowed-under by the avalanche of glitzy presentation of all that is new and expensive.Never has the expression ‘out of sight, out of mind’ been more apt.

Definition: New drug. A drug about which the adverse effects and limitations are not yet known, used by the sub-species of patients more properly called ‘guinea-pigs’, and administered by sub-species of doctor called quacks, and which is still ‘in patent’. Ken Gillman 2017 (in the spirit of Ambrose Bierce).

Beware of doctors who habitually prescribe the newest drugs, especially if that is in the context of them impressing on you (usually without subtlety) how up-to-date they are: they almost certainly know next-to-nothing about the pharmacology of the drug.

It is clear that patients and their relatives and carers need to inform themselves from reliable sources — I have written about how to do that here —  such as this, and make sure that their doctors do the right thing.

Lithium is an amazing and under-used drug, but it must be used competently.

As a review by Kessing (Denmark) recently documented, ‘major changes took place in drug prescriptions during the study period (2000 – 2011). The decrease in the use of lithium and the constant high use of antidepressants, do not align with recommendations from international guidelines’ (5).

Hayes in the UK (7) found that lithium use was little changed, but use of second generation antipsychotics, and valproate, increased dramatically.

The relative paucity of attention paid to lithium is also reflected in basic research.

In perspective

Lithium has been widely used for 50 years, it is still the best ‘mood stabiliser’, and it is still the only drug to have a legitimate claim on the term ‘mood stabiliser’: other drugs staking a claim to that crown are illegitimate imposters. Lithium is the only drug clearly demonstrated to improve both acute mania and acute depression (albeit rather slowly) as well as being good long-term prophylaxis for both phases of the illness —  and it substantially reduces long-term hospital readmission rates and suicide.

The only such drug. Unique.

Gitlin has recently discussed reasons why people might avoid lithium (8), which highlight how easy it is for doctors to persuade themselves not to bother with it, even when it is clearly the best option.

I can hear those doctors now, ‘It's just so much trouble, you have to do all these blood tests, and remember to check people's thyroid and … ‘. Response: ‘so what justifies you charging fees of hundreds of dollars an hour then?’

There is still much we do not know about its therapeutic and toxic effects. Recent advances, outlined below, are a reminder of the slow and hard-won advances in knowledge. Toxic effects from Lithium are a major cause of negligence actions against doctors. Levels between 0.4 and 0.8 mmol/L are usually suitable for prophylaxis, but toxicity is possible even within that range. Above 0.8 even more close and expert supervision is mandatory.

Despite its low therapeutic index (i.e. small difference between a good dose and a nasty dose) and some medium-term problems and toxicity, it remains a unique and invaluable drug for serious cases of ‘classic’ BPD — it is a drug that can do what no other drug can — render people completely free from episodes of a potentially fatal and life-destroying disorder.

Who responds to lithium: bipolar, unipolar, or both?

The ‘classic’ manic-depressive illness-course, of recurrent episodes of mania and depression alternating with periods of remission, commonly exhibits good long-term mood stability with lithium. About 35% of those diagnosed with manic-depressive illness (BPD***) have an excellent response to long-term lithium (9, 10).

*** I still prefer the term ‘manic-depressive illness’, to BPD — I think the view that DSM has been a negative influence in some areas is persuasive, compelling even.

Such patients achieve: mood stability, excellent prophylaxis, functional remission, and preservation of cognitive function over decades. Add the potent anti-suicidal properties of lithium (11) and you have an extra-ordinary remedy.

Good response to lithium tends to run in families, the offspring of lithium responders, if ill, often have classic episodic mood disorders, whereas the offspring of lithium non-responders tend to have non-episodic/non-fully remitting disorders, which indicates what one might predict, a genetic influence for lithium response (12).

The data from the excellent long-term studies by the group led by Jules Angst seem to me to be especially reliable and of great value. Jules is now in his 9th decade and has received many awards for his research, many rightly regard him as a giant in the field.

Angst has published evidence about the lifetime risk of apparent ‘unipolar’ severe depression (melancholic features) developing mania during the future course of their illness, and stated: ‘every new episode of depression brings a new risk for mania; more than half of our severe mood disorder cases became bipolar. The risk of depression developing into bipolar disorder remains constant lifelong’ (13).

It seems that ‘bipolar’ and ‘unipolar’ depression do not separate cleanly — but some features may predict bipolarity sufficiently well to suggest that a proportion of seemingly unipolar depressives will benefit from lithium. An interesting question is: do ‘true’ unipolar cases respond to lithium, or only those who are ‘genetically’ bipolar, but yet to manifest that? Indeed, that may be a meaningful issue only insofar as it predicts something useful, like lithium response, or worsening of illness-course precipitated by AD drugs.

Recent papers (14, 15), one looking at the high-risk time for females, the post-partum phase, conclude: ‘Psychotic symptoms, atypical features, mixed depression, younger age at onset, high number of prior episodes, episodes of short duration, switches on antidepressants, seasonality of mood episodes, as well as mood episodes with free intervals, were found to be more frequent in first episodes of postpartum depressives’.

So, if antidepressants induce mood lability and irritability, or there are mixed features and (hypo)manic symptoms, then it is likely to be correct to regard such cases as bipolar and possibly lithium responsive.

The features distinguishing bipolar from unipolar illnesses have been clarified by Prof Parker and colleagues (16-19) and are essentially those of prototypic melancholia: e.g. psychomotor retardation, difficulty thinking, early morning awakening, diurnal variation (worse in morning), psychotic features (20); one can add, rapid illness onset, brief episodes, rapid recovery to wellness, and post-natal onset.

Patients response to ECT may also be informative: bipolar illnesses respond a little more rapidly. Apparently unipolar ECT-responsive cases seem to benefit from post-ECT lithium prophylaxis (even though they do not exhibit post-ECT ‘hypomania’.

Information from these perspectives therefore paints a coherent picture.

Tiihonen’s large sample (124,000) followed up over 7 years very strongly supports long-term use of lithium in ‘unipolar’ depression (21-23)where prophylaxis with lithium was associated with a much lower risk of re-admission to hospital, whereas antidepressants and antipsychotics were not associated with any reduced risk of readmission to hospital.

Lithium may occupy a special position in that it has some, albeit slow, action to normalise mood in its own right in both acute unipolar & bipolar illness, and also a relapse preventing property that seems more than, or different to, just ongoing AD effectiveness — is that a meaningful and valid distinction?

The genetics of lithium response

The genetics of lithium response and manic-depressive illness is getting close to take-off speed. Doctors have been naïve and over-optimistic about genetics in mental illness. However, we are now getting larger sample sizes of genome-wide association studies (24-28) and some sort of progress may be hoped for. However, we should be very cautious about making premature suppositions and remind ourselves that genotype to phenotype is likely to be much more complex and environment responsive (epigenetics) than most researchers presently imagine. It will be salutary for many people to read, or re-read, the cautionary opinions of the eminent biologist, the erstwhile Agassiz professor at Harvard, Richard Lewontin (29) whose thoughts from 25 years ago remain as sagacious now as they were then.

Recent considerations

Evidence that it is important to attribute greater clinical significance to the adverse and toxic effects (e.g. on thyroid, parathyroid, and kidney) resulting from ‘therapeutic’ levels of lithium has continued to accumulate (30-32). These need careful consideration in the balancing equation of illness morbidity vs drug adverse effects — but as the famous Professor Jamison (herself a BPD sufferer) has expressed it ‘Lithium is not an easy drug, but neither are mania and depression easy illnesses to have or to treat’ (33).

Hypothyroidism

Hypothyroidism is especially common in females over 40 yrs (~20%). See ‘monitoring’ below, which is especially important since hypothyroidism is associated with depression and rapid cycling (34). Patients with hypothyroidism whilst on lithium should be prescribed thyroxine (35).

Ultrasound shows the prevalence of goitre is around 50 % (36).

Parathyroid disorders

In the above-mentioned book ‘The science and practice of lithium therapy’ Prof Goodwin from Oxford (31) notes the increasing recognition of the elevated incidence of parathyroid disorders in lithium treatment. Calcium should be measured at baseline and at least annually whilst lithium therapy continues (37) —  see table.

Nephrogenic diabetes insipidus

Polyuro-polydipsic syndrome is usually well tolerated and does not require any treatment. NDI (nephrogenic diabetes insipidus) is common (up to 50%), dose related, may be progressive as well as irreversible, and increases risk of serious central nervous system toxicity. Polyuria is probably worse if lithium is given in divided doses (38), and a single nigh-time dose makes serum level (12 hrs post-dose) monitoring simpler. For polyuria, minimising level, and if that fails amiloride, may help.

Polyuria is probably worse with higher plasma levels and it can precipitate serious plasma volume depletion and hence both reduced glomerular filtration rate (GFR) and reduced fractional excretion of lithium (FE Li). It may be a harbinger of more serious renal disease.

Lithium-Induced Nephropathy

Even when serum lithium concentrations are maintained within the therapeutic range, the glomerular filtration rate (GFR) falls slightly in about 20 % of patients (39).

It is established that long-term lithium can induce chronic tubule-interstitial nephropathy leading to renal failure, even in the absence of episodes of lithium intoxication.

Lithium in pregnancy

Discontinuation of lithium before and during pregnancy is associated with a high risk of recurrence. Similarly, suicide risk increases markedly during the 12 months after discontinuation. Since the ‘teratogenic’ risk is not high, serious consideration should be given to continuing it — appropriate texts need to be consulted about the details of such decisions and procedures.

Preparations and dosing intervals

Tondo (40) suggests that the ‘slow-release’ formulation of lithium has several advantages, including consistent serum lithium concentrations, fewer adverse events, and improved adherence to therapy. However, it is unclear that serum level-variation is very relevant when it does not reflect brain levels, and some important SEs, like polyuria are less with a single ordinary ‘fast release’ preparation. After all, we are treating the brain, not the blood.

So, if tolerated, a single daily evening dose of ‘fast release’ may be best. Compared to a multiple dose, or slow-release, a single-dose regimen may induce less polyuria and thus reduces the long-term risk of renal damage (41).

Heterogeneous lithium distribution in rat brain regions at therapeutic dosages after prolonged treatment has been reported (42) and this is a reminder that there is still considerable uncertainty about the relationship between blood levels and brain levels in humans.

Neuroprotection and other benefits

I am continually surprised by how few doctors know that lithium produces a mild leucocytosis. Lithium has a number of beneficial properties, including haematological (proliferation and maintenance of mesenchymal stem cells — hence leucocytosis), antiviral and neuroprotective effects. All these are connected with the neuroprotective and neurotrophic effects of lithium, reflected in an improvement in synaptic plasticity promoting cell survival and inhibition of apoptosis (43-45).

It remains important to ascertain which of these effects are recurring at what levels of lithium ingestion. This is especially so because of the ridiculous claims thatlithium in drinking water reduces suicide. I have criticised the increasing numbers of papers on this subject elsewhere, and it is a pity that such nonsense is diverting activity from real, interesting and serious effects.

Weight

It has always been recognised that lithium increases body weight; but a reminder of that fact appears desirable in view of how few patients are actually weighed prior to treatment.

Good clinical practice

I should note here that I did practice as I preach. Long before all this became an issue I had instituted in my hospital & private practice written guidelines and instructions for the monitoring of lithium treatment for patients, and issued guidelines to all referring doctors.

A majority of cases of toxicity result primarily from insufficient medical care and supervisory management of treatment, not from over-dose or drug interactions (46).

Written procedures & guidelines & instructions for all those clinics, hospitals & medical practices taking responsibility for care of patients on lithium, are a priority and a benchmark for 'good clinical practice'.

Levels between 0.4 and 0.8 mmol/L are usually most suitable for prophylaxis; but major side effects, and even toxicity, can occur within that range.

Advisable monitoring during lithium treatment

This table is from Professor Goodwin’s group at Oxford (31) and is in accord with the most recent UK National Institute for Health and Care Excellence (NICE) recommendations (47).

Baseline tests Pre-Rx Long-term monitoring
Lithium levels 3  monthly
Renal function (eGFR) Yes 6 monthly
Thyroid (TSH, T4, T3) Yes 6  monthly
Thyroid autoantibodies Yes If TFTs abnormal
Calcium Yes 12  monthly
Weight and BMI Yes 6  monthly
ECG Yes If toxic, or cardiac sx
Counselling teratogenic risk Yes Yearly, if of reproductive age

Taking Lithium for anything less than 2-3 years may increase, rather than decrease, overall morbidity, especially if Lithium is stopped suddenly, because of the risk of rebound mania. Suddenly means within 2 weeks. I suggest reducing by 25% of the dose, or 250 mg, every 6 - 8 weeks if it is to be ceased.

Miscellaneous comments

The superior prophylactic, compared to acute, efficacy of lithium indicates that lithium response is a long-term phenomenon — could it involve changes in receptor sensitivity or turnover, or epigenetics? Incidentally, lithium does alter the way receptors develop super-sensitivity, and sub-sensitivity, in response to agonists and antagonists (48-54). But, as one can see from the dates on these papers, they are all older, and people seem to have lost interest in that phenomenon, for reasons I do not know. I was interested to see there was no comment about that in the above-mentioned book edited by Mahli et al. It has always been my view that insufficient notice has been taken of this phenomenon, and that appears not to have changed. Am I missing something, or are they missing something?

‘Endogenous’ lithium levels

Normal lithium intake from food and liquids is low, less than one milligram per day. Lithium is sometimes referred to as an ‘ultra-trace’ element. Serum lithium levels resulting from this normal dietary intake are low, around 0.0003 mmol/l, (1 mmol/l = 6.94 mg/l). Normal hospital laboratory tests are nowhere near sensitive enough to measure such low levels.

Some sources of mineral spring water from rock-strata containing rocks (pegmatites) with high lithium content can contain as much as 10 mg/L, and typical bottled ‘mineral’ water (0.01 mg/l) is considerably higher than typical ‘municipal’ tap water (0.002 mg/l). A full discussion with detailed data on this subject is contained other commentaries, here and here.

About 10% of the total dietary intake of lithium comes from tap water: that is why it is nonsensical to propose a connection between lithium in tap-water, and suicide. Yet, there are a dozen or so papers claiming to find one — now you know why my favourite paper is: ‘Why most published research findings are false’ {Ioannidis, 2005 #7546}.

The first-line therapy

Evidence provides very strong support for the use of lithium as first-line therapy in bipolar disorder especially in those at risk of suicidal behaviour (55).

Unipolar depression

Its long-term use in unipolar depression probably has major advantages for many patients in view of the well-established lower hospital readmission rate, and the highly effective reduction in the suicide statistics. I would suggest that anyone has had two serious episodes, of the degree that might have required, or has required hospitalisation, or — for females — a post-partum episode, or has had serious suicidal intent on one or more occasions, should seriously consider long-term lithium prophylaxis.

Mortality & suicide

It is easy for doctors to forget the very substantial increases in the standard mortality rate for patients suffering these severe illnesses, not to mention the considerable increases in general morbidity (56-62).

These issues need to be faced up to, recognised and discussed — something many doctors avoid doing because they do not know how to talk about death.

Acute symptoms

At the commencement of treatment, higher lithium plasma levels are used by some people to treat acute symptoms, but I would recommend the more rapid improvement that high-dose Valproate (30 – 60 mg/kg per day — much higher than most people give), which is much under-used in acute mania.

Lithium plasma levels should be measured weekly, initially, and stabilised at 0.6–0.8 mmol/L according to ‘NICE’ — with whom I do not always agree (47). Levels as low as 0.4 may be suitable for some, and in view of the heightened appreciation of long-term adverse effects, it is especially important to use the minimum effective dose.

Research efficacy and clinical effectiveness

There is a gap between research efficacy and clinical effectiveness, and that is related to adherence — so discussion and education are paramount. If those who have to swallow the tablets are not 100% informed and enthusiastic then long-term success is unlikely.

The concern that lithium is less effective when it is reintroduced after treatment discontinuation is not supported by recent data.

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