 is associate professor of psychiatry at Harvard Medical School and Co-Director, US Department of Veterans Affairs National Bipolar Disorder Telehealth Program. 

David N. Osser, MD

frequently receive polypharmacy, with up to 20% of patients getting 4 or more bipolar medications.

 Problematic drug-drug interactions occur often, impacting effectiveness or safety. They can be pharmacokinetic or pharmacodynamic. Yet these interactions receive little attention in the various practice guidelines and algorithms for the psychopharmacologic management of bipolar disorder. Some of these will be summarized here and in a subsequent article.

—especially olanzapine, quetiapine, and clozapine—can cause even more weight gain when added to valproate.

Lithium is well known to interfere with the synthesis and release of 

 hormones and, in the brain’s effort to compensate for this, thyroid-stimulating hormone will increase. Periodic monitoring is required. What is not so well known is that carbamazepine (CBZ) decreases T4, possibly by induction of the UGT metabolizing enzyme, which exacerbates or hastens the onset of hypothyroidism.

 Thus, the combination of lithium and CBZ may present additive risks. Quetiapine also has some evidence of causing thyroid dysfunction.1

Lithium and anticonvulsants—especially valproate and CBZ—produce a metabolic-type or action tremor (ie, it is worse when doing an action like extending the arms—similar to benign familial essential tremors and tremors associated with hyperthyroidism, electrolyte abnormalities, and alcohol intoxication and withdrawal). When these medicines are used in combination, the severity or likelihood of tremor increases.

Antipsychotics—especially the older neuroleptics and risperidone/paliperidone—produce 

 (resting tremors—slower than metabolic tremors, rhythmic, typically 4 to 6 beats per second).

 Lithium seems to increase antipsychotic-induced Parkinsonian tremors by a not-well-understood mechanism.

Antipsychotics that raise prolactin (eg, risperidone, paliperidone, and most first-generation antipsychotics) increase osteoporosis risk through a pharmacodynamic effect. For this reason and others, guidelines now recommend routine monitoring of 

 Selective serotonin reuptake inhibitors (SSRIs), which are usually not recommended in bipolar patients but often used, also increase osteopenia by a different mechanism involving serotonin. With use of both agents, one can expect an additive harmful effect on bone metabolism.

CBZ also causes osteoporosis through its effect to induce the metabolism of vitamin D. Thus, the combination of CBZ with the prolactin-inducing antipsychotics or with SSRIs, or all three in combination, may produce additive bone harms over the long term.

 But here’s some good news: Lithium may protect from osteoporosis. The use of lithium in combination with antipsychotics and/or SSRIs could reduce the risk associated with the other agents. Better still: Use lithium alone for your patients with bipolar disorder if you can.

Watch out for drug-drug interactions with combinations involving ziprasidone, haloperidol, citalopram, escitalopram, quetiapine, risperidone, and lithium.

is associate professor of psychiatry at Harvard Medical School and codirector, US Department of Veterans Affairs, National Bipolar Disorder Telehealth Program, in Brockton, Massachusetts. The author reports no conflicts of interest concerning the subject matter of this article.

Possible pharmacodynamic and pharmacokinetic drug-drug interactions that are likely to be clinically relevant and/or frequent in bipolar disorder.

2. Osser DN. Neuroleptic induced pseudoparkinsonism. In: Joseph AB, Young RR, eds. 

Movement Disorders in Neurology and Neuropsychiatry, 2nd Edition

Prolactin monitoring in first-episode psychotic patients.

4. Hindley G, Gall N. QT interval prolongation. In: Taylor DM, Gaughran F, Pillinger T, eds. 

The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Articles

Up to 20% of patients with bipolar disorder have 4 or more medications, so it is important to be aware of these common drug-drug interactions.

Drug-Drug Interactions in Patients with Bipolar Disorder

Patients need to be educated frequently about what can increase or decrease their lithium levels, leading to either toxicity or loss of effectiveness. Prescribers need to be reminded as well.

The following are some common circumstances that can increase lithium levels (instruct patients to inform you of any symptoms and get extra levels in these situations):

Dehydration (eg, from vomiting or diarrhea, as may occur in acute gastroenteritis)

Reduced renal filtration rate (eg, in glomerulonephritis and diabetic nephropathy; also age related)

Thiazide diuretics (eg, hydrochlorothiazide) can produce increases from 25% to 400% (very unpredictable).

Nonsteroidal anti-inflammatory drugs (NSAIDs; eg, ibuprofen, naproxen, meloxicam) and probably COX-2 inhibitors (eg, celecoxib, diclofenac) can increase levels 10% to 400% over the course of days to months.

Angiotensin-converting enzyme (ACE) inhibitors (eg, lisinopril, enalapril) can induce up to a 400% increase over several weeks.

Angiotensin II inhibitors (eg, losartan, valsartan) probably prompt similar effects to ACE inhibitors.

The following can decrease lithium levels:

Mania may cause levels to go down 50% despite confirmed adherence.

 The mechanism is unclear, but it might be that lithium goes into the intracellular compartment during mania. If you increase dose to improve the plasma level, toxicity symptoms can appear—or they may appear after the mania remits and the lithium returns to the extracellular space.

Caffeine may promote renal excretion of lithium.

The following have little effect on lithium levels

Amiloride is a potassium-sparing diuretic and sometimes does raise levels (need to monitor).

Sulindac is an NSAID that may or may not raise levels (need to monitor).

 we discussed the importance of keeping maintenance lithium levels in the range of 0.6 to 0.8 mEq/L as well as avoiding even brief occurrences of levels more than 1.0 to minimize the risk of long-term kidney impairment.

During meetings with patients, it is important to give frequent reminders of the aforementioned factors that affect levels so that patients will be more likely to call and inform prescribers and to have lithium levels drawn when necessary. Temporary adjustment of doses while waiting for levels (or if it is impossible to get levels) may be advised in some cases.

is associate professor of psychiatry at Harvard Medical School and codirector, US Department of Veterans Affairs, National Bipolar Disorder Telehealth Program, in Brockton, Massachusetts. He is also an Editorial Board member for 

. The author reports no conflicts of interest concerning the subject matter of this article.

The Maudsley Prescribing Guidelines in Psychiatry, 14th Edition

Mood-dependent changes of serum lithium concentration in a rapid cycling patient maintained on stable doses of lithium carbonate

3. Mester R, Toren P, Mizrachi I, et al. 

Caffeine withdrawal increases lithium blood levels

4. Ciraulo DA, Shader RI, Greenblatt DJ, Creelman W. 

. Lippincott Williams & Wilkins; 2006:272-275.

Tips for lithium dosing for optimal renal safety

Here are a few reminders to help avoid both toxicity and loss of effectiveness.

Lithium Levels—What Increases and Decreases Them?

Bipolar Disorder: Sorting Out Comorbidities

Slideshows

Because patients with bipolar disorder often have underlying comorbidities, a thorough diagnosis is imperative. 

Nephrotoxicity is a well-known adverse effect of lithium. Monitoring for nephrotoxicity and using 

 with great caution in patients with renal impairment are standards of care.

The estimated glomerular filtration rate (eGFR) has become an easily available routine measure for baseline and periodic monitoring of kidney function in patients on lithium.

 Laboratories report eGFRs of less than 60 mL/minute/1.73 m

 as abnormal and indicating risk of chronic kidney disease (CKD). Stage 3 CKD, associated with an eGFR of 45 plus or minus 14 mL/minute/1.73 m

, is defined as a level of impairment with significant potential for kidney failure and death during a 5-year period. One would usually want to avoid lithium, or consider reducing or discontinuing it, if the eGFR is between 45 and 59 mL/minute/1.73 m

 Bipolar Update, we discussed ways of dosing 

 and maintaining levels of lithium to minimize risk of kidney harm.

 These included using the immediate-release formulation (rather than long-acting versions), prescribing the full dose at night, keeping maintenance levels no higher than 0.6 to 0.8 mEq/L, and avoiding levels higher than 1.0 mEq/L at any time.

GFR decreases with age, so not all reductions of eGFR during long-term lithium use are due to lithium. Questions have been raised about the longstanding adoption of a fixed threshold of less than 60 mL/minute/1.73 m

 for an abnormal eGFR for patients of all ages. It has been proposed that the thresholds should be 75 mL/minute/1.73 m

 for patients under age 40, 60 mL/minute/1.73 m2 for those aged 40 to 65 years, and 45 mL/minute/1.73 m

In a recent study, investigators evaluated outcomes associated with CKD when defined by a fixed (< 60) threshold vs these age-adapted eGFR thresholds.

 Utilizing a population-based cohort of patients in the province of Alberta, Canada, investigators found, as expected, that CKD was diagnosed much more often in older adults using the standard threshold of less than 60 compared with using a 45 mL/minute/1.73 m

 threshold. There were 2356 new cases per 100,000 person-years with the 60 mL/minute/1.73 m

 threshold vs 714 with the 45 mL/minute/1.73 m

 threshold. However, 75% of patients with eGFRs from 45 to 59 mL/minute/1.73 m

 were aged 65 or older and had normal or only mild albuminuria. The 5-year risks of kidney failure and deaths among these older adults were similar to those of a control group of non-CKD elderly patients with eGFRs from 60 to 89 mL/minute/1.73 m

 was 0.12% in both groups. The investigators concluded that the current fixed eGFR criterion seems to result in overdiagnosis of CKD in this aging population. They likely suffered unnecessary evaluations and interventions when their problem was only age-related reduction in eGFR.

 would seem to be that older adults and some other patients with eGFRs of 45 to 59 mL/minute/1.73 m

 do not necessarily have CKD. Clinicians should evaluate these patients for proteinuria before making that diagnosis. Of course, close consultation with a kidney specialist would be advised regarding decisions about lithium use. However, it may be reasonable to start or continue to use lithium in more patients than was done prior to the emergence of this new perspective on the meaning of eGFRs.

Younger patients, in contrast, were often underdiagnosed with CKD using the 60 mL/minute/1.73 m

 threshold. The study found 14 vs 91 new cases of CKD per 100,000 person-years with the 60 and 75 mL/minute/1.73 m

 thresholds, respectively. The absolute rate of CKD was low. Still, it would seem prudent to remember the Alberta data and consult with a renal specialist if the eGFR is below 75 mL/minute/1.73 m

 in younger patients. Notably, however, studies of lithium maintenance in younger patients with bipolar disorder have not found declining eGFRs.

is an associate professor of psychiatry at Harvard Medical School and codirector of the US Department of Veterans Affairs’ National Bipolar Disorder Telehealth Program in Brockton, Massachusetts. The author reports no conflicts of interest concerning the subject matter of this article.

The Maudsley Prescribing Guidelines in Psychiatry. 14th Edition. 

Lithium and eGFR: a new routinely available tool for the prevention of chronic kidney disease.

Tips for lithium dosing for optimal renal safety.

4. Delanaye P, Jager KJ, Bökenkamp A, et al. 

CKD: a call for an age-adapted definition.

Accounting for age in the definition of chronic kidney disease.

6. Clos S, Rauchhaus P, Severn A, et al. 

Long term effect of lithium maintenance therapy on eGFR in patients with affective disorders: a population-based cohort study.

Chronic Kidney Disease and Lithium—A New Perspective

(This is the third part of the How To Diagnose Bipolar Disorder series—Ed.)

Have you had difficulty with differential diagnosis when the patient has manic symptoms and psychosis? In 2013, the DSM-5 made the issue clearer with significant changes in the criteria defining the quantity and nature of mood symptoms in these diagnoses. As a result, more patients will be diagnosed with schizophrenia compared with when using DSM-IV in either the TM or later “Text Revised” TR version. I will propose some of the implications for psychopharmacology.

In the schizophrenia D criteria in DSM-5, the patient should have no mood episodes (ie, meeting full criteria for mania or depression) during the active phase of the illness, or, if the patient has episodes, those episodes occur during a minority (ie, up to 50%) of the total duration of the illness (active and residual phases). In other words, a patient with schizophrenia can have a full manic syndrome present for up to 50% of the time, as long as the other schizophrenia criteria are met. Those criteria include, from the A criteria, positive symptoms during the acute phase; the B criteria of illness duration of at least 6 months of the active and residual phases; the C criteria of deterioration in functioning compared to premorbid levels; and the E criteria of no explanation of it from a substance or medical illness.

In the DSM-IV D criteria for schizophrenia, the requirement was that any mood episodes had to be brief in duration compared with the duration of the illness. An example of “brief” was a 5-week period of mania or depression in a patient who was ill for 4 years, which would translate to having a mood syndrome present 2.5% of the time. So, with DSM-IV, individuals with schizophrenia could not experience much time with any mood syndrome to meet the criteria. If mood syndromes were present longer than 2.5% of the time, the diagnosis would be schizoaffective disorder or bipolar with psychosis.

However, the DSM-5 criteria for schizoaffective disorder offer the mirror image of the D criteria for schizophrenia: Here, the individual must meet criteria for a mood syndrome for the majority (ie, 50% or more) of the total time that they have been ill. In DSM-IV, it had to be substantial (ie, more than brief [2.5%]). Diagnosis also requires the other schizoaffective criteria, including 2 weeks of psychosis in the absence of prominent mood symptoms. Here, the term 

, meaning that there cannot be any prominent symptoms—much less the full syndrome—of mania or depression present for those 2 weeks.

There seem to be very few patients who meet these DSM-5 criteria for schizoaffective disorder, which require that they be in a mania (or depression) for the majority of the time and also have psychosis without any significant symptoms of a mood disorder for 2 full weeks. Making it tougher to diagnose schizoaffective disorder was probably intended by the DSM-5 authors. The evidence they considered suggested that the disorder, as defined in DSM-IV, did not exist;

 they wanted to eliminate it. They retained it because of pushback from field trials, with practicing psychiatrists who largely wanted to keep schizoaffective disorder in the manual.

Notably, study results have shown that when the DSM-IV criteria for schizoaffective disorder were in use (1994-2013), clinicians did not seem to use it for diagnoses.

 They overdiagnosed it using unspecified criteria. Also, study results found that patients diagnosed using the criteria very often evolved over time to having a schizophrenia diagnosis, whereas schizophrenia diagnoses under DSM-IV tended to be stable over time.

 Accordingly, with the new, more inclusive DSM-5 criteria for schizophrenia, the diagnosis should continue to be stable.

How about the diagnosis of mania with psychosis? In psychotic mania (in DSM-IV and DSM-5), the psychosis appears only during the time the patient is meeting criteria for mania, not after it as in schizoaffective disorder. Usually, the psychosis develops during the most severe part of the mania and tends to resolve early as the episode improves, and before the rest of the manic symptoms resolve.

Now that you have an accurate diagnosis per DSM-5, what is the psychopharmacology treatment? If the diagnosis turns out to be schizophrenia, there is no demonstrated value to adding non-antipsychotic mood stabilizers (like lithium or valproate) to the antipsychotic for the manic component, according to the evidence reviewed in the Schizophrenia Patient Outcomes Research Team (PORT) guidelines.

 These additions only potentially contribute adverse effects. The usual psychopharmacology algorithm of employing 2 adequate monotherapy trials of antipsychotics followed by consideration of clozapine probably still applies for DSM-5 schizophrenia. If the diagnosis is bipolar with psychosis, you can use those traditional mood stabilizers as well as antipsychotics. Study results show that psychotic mania responds just as well to either class of drugs.

But what if the patient meets the DSM-5 criteria for schizoaffective disorder, bipolar type? We do not know how to treat it, just as we did not know how to treat DSM-IV schizoaffective disorder, bipolar type. There are almost no studies, no algorithms to consult, no FDA-approved options (although some paliperidone products did manage to get the only FDA approval for schizoaffective disorder). There is still serious doubt that the condition even exists as a valid entity, and it is likely that the current criteria capture only some patients who belong in either the schizophrenia spectrum or the bipolar spectrum.

It is suggested that you treat with your best psychopharmacology algorithm for schizophrenia or for bipolar with psychosis, depending on which diagnostic category best represents the patient’s presentation. If the results are unsatisfactory, try switching to your algorithm for the other diagnosis. This may produce better results than improvising with pure guesswork.

is co-director of the VA National Bipolar Disorder Telehealth Program and an associate professor of psychiatry at Harvard Medical School at the VA Boston Healthcare System.

1. Kotov R, Leong SH, Mojtabai R, et al. 

Boundaries of schizoaffective disorder: revisiting Kraepelin

2. Cheniaux E, Landeira-Fernandez J, Lessa Telles L, et al. 

Does schizoaffective disorder really exist? a systematic review of the studies that compared schizoaffective disorder with schizophrenia or mood disorders

Current issues on schizoaffective disorder

4. Jäger M, Haack S, Becker T, Frasch K. 

Schizoaffective disorder—an ongoing challenge for psychiatric nosology

The stages of mania. a longitudinal analysis of the manic episode

6. Kreyenbuhl J, Buchanan RW, Dickerson FB, Dixon LB; Schizophrenia Patient Outcomes Research Team (PORT). 

The Schizophrenia Patient Outcomes Research Team (PORT): updated treatment recommendations 2009

The psychopharmacology algorithm project at the Harvard South Shore Program: an algorithm for acute mania

Have you had difficulty with differential diagnosis when patients have manic symptoms and psychosis? One doctor discusses the related DSM-5 criteria changes and some of their implications for psychopharmacology.


Mania With Psychosis vs Schizophrenia vs Schizoaffective Disorder, Bipolar Type

 have focused on lithium’s advantages. The well-known downsides, including renal impairment, have also been discussed. However, a recent consultation reminded me that there is an infrequent, but important, toxic effect of lithium that deserves increased awareness: the Syndrome of Irreversible Lithium-Effectuated Neurotoxicity, or SILENT.

 First named in the 1980s, SILENT was diagnosed in 90 case reports in peer-reviewed publications as of 2005, starting in 1949 when lithium chloride was being used as a substitute for table salt.

The clinical profile of SILENT varies, but persistent cerebellar dysfunction is the most common finding, with extrapyramidal symptoms also typically present. Many of these cases involve insidious progression in patients on normal or low therapeutic levels of 

. The first sign may be decreased alertness or slight apathy, followed by muscular rigidity or fasciculations and mild ataxia. These symptoms increase and become severe, and then impaired consciousness with a stupor-like presentation can develop.

When lithium is stopped, some or all of these symptoms may persist beyond 2 months, with some reports describing continued symptoms for 5 years. Most cases have residual impairments such as ataxia and dysarthria that continue for 1 year. Sometimes there is persisting cognitive dysfunction with memory loss and other symptoms of dementia. In other cases, additional atypical symptoms accompany the core features, including nystagmus, papilledema, and choreoathetoid movements suggestive of tardive dyskinesia.

SILENT’s cause is unknown. Demyelination has been found on biopsy of peripheral nerves and may occur in the cerebellum and elsewhere.

 This may account for the persistence of the neurological sequelae.

Precipitating or predictive factors may include diagnosis of schizoaffective disorder, marked psychosis, abnormal EEG prior to treatment, preexisting neurological illnesses including Alzheimer disease, and fever—especially high fever.

 Readers may recall the famous 1970s cases of neurotoxicity arising from the use of lithium plus haloperidol.

 All patients in those cases had very high fevers and high lithium levels, and they are now thought to have had cases of SILENT. Some other possible contributing factors could be hypertension, heart failure, rapid lowering from high lithium levels, and epilepsy.

To prevent SILENT, it may be helpful to avoid high lithium levels through regular and frequent monitoring (eg, every 4-6 months). If symptoms develop, 

. Treat persisting symptoms with appropriate physical rehabilitation and cognitive training as you would for dementia.

The other side of the coin on lithium neurotoxicity, as discussed in a previous column,

 is the positive neurotrophic effects of lithium that benefit many patients. In a recent pilot study, for example, 12 patients recovering from stroke were prescribed open-label lithium for 60 days (target levels, 0.4-0.6 mEq/L). Gray matter volume as measured by MRI increased numerically (but not significantly; P = .07), and there was a significant correlation between higher lithium dose and gray matter volume increase (P = .004) and improved verbal memory (P = .05).

In conclusion, lithium’s benefits to brain health are substantial, but there are rare cases of serious toxicity that should be detected as early as possible.

is an associate professor of psychiatry at Harvard Medical School and codirector of the US Department of Veterans Affairs’ National Bipolar Disorder Telehealth Program, in Brockton, Massachusetts. The author reports no conflicts of interest concerning the subject matter of this article.

The syndrome of irreversible lithium-effectuated neurotoxicity. 

2. Hanlon LW, Romaine M III, Gilroy FJ, Deitrick JE. 

Lithium chloride as a substitute for sodium chloride in the diet; observations on its toxicity.

Lithium carbonate, haloperidol, and irreversible brain damage.

5. Sun YR, Herrmann N, Scott CJM, et al. 

Lithium carbonate in a poststroke population: exploratory analyses of neuroanatomical and cognitive outcomes.

This infrequent, but important, toxic effect of lithium deserves increased awareness.