Ralph J. Koek, MD

The correct answer is E. None of the above

Only 2 medications have FDA indications for PTSD: paroxetine and sertraline. Some treatment guidelines recommend these or other antidepressants, including fluoxetine and venlafaxine, as equivalently first choice with focused CBT.

 Others regard focused CBT as having better evidence and suggest antidepressants only when therapy has failed or is not available, or in cases of severe depression.

 This reflects a number of negative randomized clinical trials (RCTs) with SSRIs, and small-to-moderate effect sizes relative to trauma-focused cognitive-behavioral therapy. It is important to note that many patients remain symptomatic and functionally impaired despite standard treatments and require alternative interventions.

There are medications with expert recommendations against their use (benzodiazepines), with uniformly negative RCTs (divalproex, bupropion, guanfacine, tiagabine), or with a mixture of both positive and negative evidence (fluoxetine, mirtaza¬pine, risperidone and olanzapine augmentation of antidepressants, topiramate). Furthermore, some commonly used pharmacologic agents have not been subject to RCTs in PTSD (citalopram, escitalopram, gabapentin, clonidine, lithium), nor have many newer agents such as levomilnacipran, milnacipran, vilazodone, vortioxetine, lurasidone, iloperidone, cariprazine, and brexpiprazole. Given the challenges in helping people with treatment-resistant PTSD, it was not surprising to find an impressive variety of alternative pharmacologic agents that have shown benefit in at least some treatment-resistant patients


1. Bajor LA, Ticlea AN, Osser DN. The psychopharmacology algorithm project at the Harvard South Shore Program: an update on posttraumatic stress disorder. Harv Rev Psychiatry. 2011;19:240-258.
2. Jonas DE, Cusack K, Forneris CA, et al. Psychological and Pharmacological Treatments for Adults With Posttraumatic Stress Disorder (PTSD). Comparative Effectiveness Review No. 92. https://www.ncbi.nlm.nih.gov/books/NBK137702/. Accessed September 29, 2017.
3. Steenkamp MM, Litz BT, Hogue CW, Marmar CR. Psychotherapy for military-related PTSD: a review of randomized clinical trials. JAMA. 2015;314:489-500.
4. Gehrman P, Harb G, Ross R. PTSD and sleep. PTSD Res Quart. 2016;27:1-10
5. Toll WA, Barbui C, Ommeren M. Management of acute stress, PTSD, and bereavement: WHO recommendations. JAMA. 2013;310:477-478.

Articles

Which medications have consistently replicated randomized placebo-controlled trial evidence of efficacy in treating symptoms that are unresponsive to sertraline or paroxetine? Take the quiz and learn more.

Mini Quiz: Treatment for PTSD

Slideshows

The author addresses some of the complexities in assessing and managing treatment-resistant PTSD.

10 Factors to Consider When Assessing PTSD

Treatment-resistant depression has been discussed widely for years, but treatment resistance in PTSD-another common, serious, disabling condition-has been less frequently addressed in the literature. While 70% of the world’s population has been exposed to a traumatic event, only 5.6% meet DSM-5 criteria for PTSD.

 Moreover, 44% of patients with a PTSD diagnosis recover even without specific treatment.

Trauma-focused cognitive-behavioral therapy (TF-CBT), such as prolonged exposure therapy, cognitive-processing therapy, or eye movement desensitization and reprocessing, has been recommended as first-choice treatment for chronic PTSD.

 TF-CBT and non–trauma-focused CBT may be equally effective post-treatment; TF-CBT has been found to be more effective at 1 to 4 months’ follow-up.

 However, there is a high dropout rate from these treatments. Two-thirds of veterans who complete cognitive-processing therapy or prolonged exposure therapy retain a PTSD diagnosis despite large within-group effect sizes

; significant sleep problems often persist, and there are less data about longer-term follow-up.

Ms. A, 55 years old, has had depression, panic attacks, insomnia, and social withdrawal that have not benefited from trials of citalopram, paroxetine, and sertraline over the past 3 years. At intake, she describes persistent grief for the past 10 years since witnessing the shooting death of her son. She is unable to describe the incident, exhibits the conviction that she is responsible for the death, and has difficulty acknowledging that her child is gone. She persistently re-experiences the traumatic event with a mixture of sadness, anger, and guilt. Her anxiety consists of extreme social avoidance and hypervigilance, and she has frequent nightmares.

Mr. B is a 66-year-old Vietnam combat veteran. Over the nearly 40 years since the Vietnam War, he has been able to work in an administrative position and raise a family, without substance use disorder, serious general medical conditions, or legal problems. On the other hand, besides his work and involvement in a Veterans Service Organization, he has engaged in little social activity with his family or otherwise-no concerts, ballgames, movies, holiday parties, etc. He has undergone multiple unsuccessful pharmacology trials. At presentation, he is taking 200 mg of sertraline and 2500 mg of divalproex daily, and 4 mg of clonazepam and 500 mg of quetiapine daily at bedtime. He has persistent insomnia, severe combat nightmares, angry hyperarousal, and hypervigilance.

 This reflects a number of negative randomized clinical trials (RCTs) with SSRIs, and small-to-moderate effect sizes relative to TF-CBT.

Related content: Mini Quiz: Treatment for PTSD

Many patients remain symptomatic and functionally impaired despite standard treatments and require alternative interventions. In a review of the pertinent literature on treatment-resistant PTSD, it was found that only 53% of 167 RCTs, open-label studies, and case series that assessed the efficacy of medication other than sertraline or paroxetine described failure of prior pharmacotherapies, and only 3% described failure of TF-CBT. The only RCT of an SSRI (paroxetine) in CBT non-responders failed to show benefit. Systematic investigation of CBT in pharmacotherapy non-responders has also received little investigation. The complexity of the literature did not permit specific recommendations about relative benefits of alternative next-step pharmacologic strategies in paroxetine/sertraline non-responders.

Recommendations for second-line pharmacotherapy vary widely among recent reviews and treatment guidelines with a second antidepressant most often recommended for initial treatment failures. Despite a large, negative 6-month multicenter RCT of risperidone augmentation of antidepressants, some-but not all-treatment guidelines recommend atypical antipsychotic augmentation when antidepressants fail.

 None recommend atypical antipsychotic monotherapy or typical antipsychotics. Most specifically mention prazosin; one guideline recommends it in conjunction with focused CBT as the best initial treatment, while others recommend it as a second-line treatment.

Most experts agree that patients with PTSD and persistent nightmares should not be regarded as treatment-refractory unless they have had an adequate trial of prazosin, which should be a minimum of 10 mg daily at bedtime, with additional daytime dosing in some patients. Prazosin may require careful titration over several months. Anticonvulsants are not supported by strong evidence, although some found the evidence for topiramate more convincing than others.

 I have seen benefit in some patients who have nightmares, although adverse effects are common.

One notable finding-unfortunately unchanged since Hamner and colleagues

 made the same observation in 2004-is that there is a dearth of evidence on lithium in PTSD, including no RCTs. This is unfortunate given associations between PTSD and suicidal behavior, anger dyscontrol, and impulsivity, which are potential targets for long-term lithium therapy. In my experience, both individuals with clear bipolar comorbidity and patients in whom bipolar NOS is more difficult to separate from severe PTSD may benefit.

D-cycloserine has been used as an augmentation strategy to enhance extinction in conjunction with exposure, with largely unimpressive, although complex, results. To date, it has not demonstrated efficacy in treatment-resistant PTSD.

 developed the Emory Treatment Resistance Interview for PTSD (E-TRIP). It does not provide an algorithm for next-step treatment but allows the clinician to generate a numerical score for degree of treatment resistance in an individual based on failure of pharmacotherapies and psychotherapies, with RCT data supporting efficacy.

 addresses some of the complexities in assessing and managing treatment-resistant PTSD. The Case Vignettes also illustrate some of these points. Ms. A’s treatment consisted of psychoeducation about the nature of PTSD followed by prolonged exposure, as well as extensive cognitive-processing therapy that addressed “survivor guilt.” After nearly 2 years, she came to accept her child’s death; recovered from her self-blame; and her depression, hypervigilance, and avoidance improved. Sleep improved with trazodone once her avoidance and hypervigilance responded to exposure. Venlafaxine, 225 mg daily, provided more benefit than SSRIs.

Mr. B required systematic medication changes over 2 years, with a final regimen of 15 mg of prazosin and 30 mg of mirtazapine daily at bedtime plus 300 mg of sertraline and 50 µg of levothyroxine sodium daily (based on exacerbations of comorbid anergic depression correlated with high-normal thyroid-stimulating hormone levels of 3.5 to 4.5 mIU/L from a baseline of 1 to 2.4 mIU/L). With this regimen, nightmares stopped and he slept 7 to 8 hours for the first time in decades. The improvement in sleep and depression permitted in vivo exposure therapy that reduced first avoidance behavior and secondarily anger and hypervigilance. He has remained essentially well now for more than 3 years, even with current doses of 200 mg of sertraline, 15 mg of mirtazapine, and 5 mg of prazosin.

PTSD is relatively unique among psychiatric disorders in requiring a specific etiology. Treatment must first address the specific individualized aspects of the trauma itself and contextualize its role in the patient’s life. Certain types of trauma can reduce the likelihood of spontaneous recovery (eg, PTSD due to medical illness

) or response to treatment: childhood abuse-related trauma, repeated or prolonged trauma, more severe trauma, and trauma associated with marked impairment of self-regulation. Combat PTSD is frequently regarded as less responsive to standard treatments than single-event civilian trauma-associated PTSD.

Comorbid substance use, severe anger dyscontrol, mood disorders, or personality disorders understandably make treatment more difficult and complex. The evidence is mixed on whether compensation seeking per se reduces the likelihood of benefit from treatment. Finally, some traumatic experiences such as disaster or terrorism (which may include losses of significant others, physical injuries, occupational and other practical alterations, or cultural dislocation) usually require interpersonal support and practical interventions.

Different components of the clinical syndrome may respond differently to different interventions. When medications are effective, they usually provide more benefit for intrusive and hyperarousal, than avoidance symptoms. Exposure therapy directly addresses avoidance, which is also improved with other forms of TF-CBT (as are intrusive and hyperarousal symptoms). To date, few trials have utilized DSM-5 criteria, which include additional symptoms (negative alterations in cognitions and emotions) to those in DSM-IV. A recent meta-analysis of 93 RCTs found that treatments effective for PTSD are also effective for improving comorbid depressive symptoms (which overlap to some extent with DSM-5 PTSD Cluster D symptoms).

Some PTSD subtypes may require specific treatments. PTSD with psychotic features, while not included in DSM-IV or DSM-5, is well recognized and is a better indication for atypical antipsychotic augmentation of antidepressants than PTSD per se.

 Complex PTSD, which includes prominent difficulties in self-regulation capacity, may respond to focused CBT but often requires a “staged” approach.

There is no “best” evidence-based treatment for all patients, and this is true for treatment-resistant PTSD. Pharmacologic management must be individualized, and the use of focused CBT in conjunction with pharmacotherapy may require careful, flexible integration, sometimes across months or years of treatment-as in Ms. A’s and Mr. B’s cases. Still, as also illustrated by Mr. B’s case, empirical data summarized in 

 may be of value in making medication changes.

There are medications with expert recommendations against their use (benzodiazepines), with uniformly negative RCTs (divalproex, bupropion, guanfacine, tiagabine), or with a mixture of both positive and negative evidence (fluoxetine, mirtaza­pine, risperidone and olanzapine augmentation of antidepressants, topiramate). Furthermore, some commonly used pharmacologic agents have not been subject to RCTs in PTSD (citalopram, escitalopram, gabapentin, clonidine, lithium), nor have many newer agents such as levomilnacipran, milnacipran, vilazodone, vortioxetine, lurasidone, iloperidone, cariprazine, and brexpiprazole. Given the challenges in helping people with treatment-resistant PTSD, it was not surprising to find an impressive variety of alternative pharmacologic agents that have shown benefit in at least some treatment-resistant patients (

). Future research may lead to agents that directly address neuropharmacologic mechanisms of extinction in the amygdala including glutamate/NMDA modulators.

 At this time, evidence on the risk-to-benefit ratio for marijuana/cannabinoids does not justify a recommendation for treatment-resistant PTSD.

In concert with direct neuromodulatory approaches for other refractory psychiatric disorders, some patients have benefited from acupuncture, ECT, repetitive transcranial magnetic stimulation (rTMS), vagus nerve stimulation, transcranial direct nerve stimulation, stellate ganglion block,

 trigeminal nerve stimulation, and amygdala deep brain stimulation. None of these are FDA approved, although investigations are ongoing. The Veterans Administration Department of Defense PTSD Treatment Guideline provides a B level recommendation for ECT and rTMS as treatments for patients with “chronic, severe, medication- and psychotherapy-resistant PTSD.”

While RCTs of medications typically involve weekly to bimonthly follow-up visits, and prolonged exposure therapy and cognitive-processing therapy require weekly visits for standard implementation, for many patients, such frequency of visits is limited by practical considerations (eg, cost, work obligations). This was true for Ms. A and Mr. B. For many patients like Ms. A and Mr. B, who have suffered for years, it may not be surprising to find that medication changes may take months or longer to achieve optimal benefit, and some components of focused CBT involve changes in maladaptive habits, ingrained after trauma, that take time to implement.

Dr. Koek is Staff Psychiatrist at the Sepulveda Ambulatory Care Center, VA Greater Los Angeles Healthcare System; Director of the Mood Disorders Clinic, UCLA/San Fernando Psychiatry Training Program; Clinical Professor, Department of Psychiatry and Bio-behavioral Sciences at the David Geffen School of Medicine at UCLA in Los Angeles; and Teaching Faculty at the Family Medicine Residency Program, Glendale Adventist Medical Center in Glendale, CA.

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

 Koenen KC, Ratanatharathorn A, Ng L, et al. Posttraumatic stress disorder in the World Mental Health Surveys. 

 Morina N, Wicherts JM, Lobbrecht J, Priebe S. Remission from post-traumatic stress disorder in adults: a systematic review and meta-analysis of long-term outcome studies. 

 Foa EB, Keane TM, Friedman MJ, Cohen JA. 

Effective Treatments for PTSD: Practice Guidelines from the International Society for Traumatic Stress Studies

 United States Department of Veterans Affairs. VA DoD Clinical Practice Guidelines: Management of Posttraumatic Stress Disorder and Acute Stress Reaction; 2017. 

https://www.healthquality.va.gov/guidelines/MH/ptsd/

 Bajor LA, Ticlea AN, Osser DN. The psychopharmacology algorithm project at the Harvard South Shore Program: an update on posttraumatic stress disorder. 

 Jonas DE, Cusack K, Forneris CA, et al. Psychological and Pharmacological Treatments for Adults With Posttraumatic Stress Disorder (PTSD). Comparative Effectiveness Review No. 92. 

https://www.ncbi.nlm.nih.gov/books/NBK137702/

 Steenkamp MM, Litz BT, Hogue CW, Marmar CR. Psychotherapy for military-related PTSD: a review of randomized clinical trials. 

 Gehrman P, Harb G, Ross R. PTSD and sleep. 

 Toll WA, Barbui C, Ommeren M. Management of acute stress, PTSD, and bereavement: WHO recommendations. 

 Koek RJ, Schwartz HN, Scully S, et al. Treatment-refractory posttraumatic stress disorder: a review and framework for the future. 

Prog Neuropsychopharmacol Biol Psychiatry

 Krystal JH, Rosenheck RA, Cramer JA, et al. Adjunctive risperidone treatment for antidepressant-resistant symptoms of chronic military service-related PTSD: a randomized trial. 

 Hamner MB, Robert S, Frueh BC. Treatment-resistant posttraumatic stress disorder: strategies for intervention. 

 Dunlop BW, Kaye JL, Youngner C, Rothbaum B. Assessing treatment-resistant posttraumatic stress disorder: The Emory Treatment Resistance Interview for PTSD (E-TRIP). 

 Ronconi JM, Shiner B, Watts BV. A meta-analysis of depressive symptom outcomes in randomized, controlled trials of PTSD. 

 Liu XH, Xie XH, Wang KY, Cui H. Efficacy and acceptability of atypical antipsychotics for the treatment of post-traumatic stress disorder: a meta-analysis of randomized, double-blind, placebo-controlled clinical trials. 

 Bernardy NC, Friedman MJ. Psychopharmacological strategies in the management of posttraumatic stress disorder (PTSD): what have we learned? 

 Steenkamp MM, Blessing EM, Galatzer-Levy IR, et al. Marijuana and other cannabinoids as a treatment for posttraumatic stress disorder: a literature review. 

 Summers MR, Nevin RL. Stellate ganglion block in the treatment of post-traumatic stress disorder: a review of historical and recent literature. 

 Villarreal G, Hamner MD, Canive JM, et al. Efficacy of quetiapine monotherapy in posttraumatic stress disorder: a randomized, placebo-controlled trial. 

 Davis LL, Davidson JR, Ward LC, et al. Divalproex in the treatment of posttraumatic stress disorder: a randomized, double-blind, placebo-controlled trial in a veteran population. 

 Raskind MA, Peterson K, Williams T, et al. A trial of prazosin for combat trauma PTSD with nightmares in active-duty soldiers returned from Iraq and Afghanistan. 

Trauma-focused cognitive-behavioral therapy, pharmacotherapy, and combinations thereof. Expert guidance here.

Treatment-Resistant PTSD

This activity offers CE credits for:
1. Physicians (CME)
2. Other

To understand the key role of lithium in the treatment of bipolar disorder.

At the end of this CE activity, participants should be able to:

1. Understand the indications for the use of lithium in acute mania and in maintenance treatment of bipolar disorder

2. Describe the evidence for lithium’s neuroprotective effect

3. Define the various safety concerns associated with the use of lithium and how they can be mitigated

This continuing medical education activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve their care for patients with mental health disorders.

CME Credit (Physicians): This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of CME Outfitters, LLC, and 

. CME Outfitters, LLC, is accredited by the ACCME to provide continuing medical education for physicians.

CME Outfitters designates this enduring material for a maximum of 

. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Note to Nurse Practitioners and Physician Assistants: AANPCP and AAPA accept certificates of participation for educational activities certified for 

It is the policy of CME Outfitters, LLC, to ensure independence, balance, objectivity, and scientific rigor and integrity in all of their CME/CE activities. Faculty must disclose to the participants any relationships with commercial companies whose products or devices may be mentioned in faculty presentations, or with the commercial supporter of this CME/CE activity. CME Outfitters, LLC, has evaluated, identified, and attempted to resolve any potential conflicts of interest through a rigorous content validation procedure, use of evidence-based data/research, and a multidisciplinary peer-review process.

The following information is for participant information only. It is not assumed that these relationships will have a negative impact on the presentations.

Ralph J. Koek, MD, has no disclosures to report.

Richard Balon, MD (peer/content reviewer), has no disclosures to report.

 staff and CME Outfitters staff have no disclosures to report.

Faculty of this CME/CE activity may include discussion of products or devices that are not currently labeled for use by the FDA. The faculty have been informed of their responsibility to disclose to the audience if they will be discussing off-label or investigational uses (any uses not approved by the FDA) of products or devices. CME Outfitters, LLC, and the faculty do not endorse the use of any product outside of the FDA-labeled indications. Medical professionals should not utilize the procedures, products, or diagnosis techniques discussed during this activity without evaluation of their patient for contraindications or dangers of use.

Questions about this activity? Call us at 

“Lithium? Do you guys still use that?”


(Referring physician, in response to my recommendation for a high-functioning 24-year-old woman with classic, familial bipolar I disorder recovering from a second post-manic depression, 2013.)

Bipolar disorder (BD) is a serious medical illness associated with high rates of attempted and completed suicide and considerable suffering as well as social, occupational, and medical morbidity. In 90% of patients, a second mood episode will develop after recovery from the episode leading to diagnosis, and long-term maintenance mood stabilizer medication is usually indicated.

For the first several decades after Cade’s 1949 discovery, lithium was the mainstay of bipolar prophylaxis. Every psychiatrist had considerable experience with its use-including the many attendant caveats.

In the past few decades, beginning with carbamazepine, then valproic acid derivatives, followed by lamotrigine, and finally the atypical antipsychotics, additional options for maintenance pharmacotherapy have become available, and lithium use has declined. At least 2 other factors have also played a role in the decline: concerns about lithium’s adverse effects/toxicity and inadequate prophylactic effectiveness for many patients.

Lithium carbonate is FDA-indicated for acute mania and maintenance treatment of BD. It is recommended as first-line therapy for maintenance in BD treatment guidelines. The effectiveness of lithium as maintenance therapy is based on trials done decades ago when it was compared with placebo, as well as on recent studies in which lithium served as the active comparator for newer agents. Recent findings support lithium over alternatives for effectiveness in long-term mood stabilization.

 However, the prophylactic benefits of lithium are significantly better for episodes of mania than for depression recurrence.

 Moreover, lithium reduces the risk of recurrence in both BD-II and BD-I.

Although lithium remains the first choice for maintenance treatment, it cannot be recommended for every patient. As with any treatment, when considering the use of lithium, the first step is to educate patients and their families about the benefits and risks and alternatives.

In terms of benefits, lithium’s clear suicide preventive value stands out. Most psychiatrists are familiar with the evidence that demonstrates that long-term lithium therapy leads to a 5-fold decrease in suicide risk compared with placebo and other active treatments.

 confirmed this benefit, although they did not find a statistically significant difference between lithium and several other mood stabilizers (carbamazepine, lamotrigine, olanzapine). In their comprehensive review, Yerevanian and Choi

 found that no agent or class of agents matched lithium’s evidence for protection from suicidal behavior in BD. Recent findings also continue to support lithium’s benefit for reducing the high medical morbidity and mortality in BD.

Another benefit that has emerged into prominence is the neurotrophic properties of lithium that may mediate a direct illness-modifying effect. BD can be viewed as a neuroprogressive disorder, and lithium has the best evidence for neuroprotection.

 Lithium’s classic “cognitive dulling” effect, with mild impairments in memory, information processing speed, and creativity, has also been empirically confirmed.

 However, these deficits were not found to progress beyond 6 years, nor were they found in excellent lithium responders.

 Although some evidence suggests that lithium’s neuroprotective effect is selective for responders, other findings suggest that it occurs independently.

 While there is evidence to support lithium’s efficacy in primary neurocognitive disorders, there is no evidence to support the efficacy of valproic acid derivatives.

Asking whether some bipolar patients are likely to benefit from lithium may help the prescribing physician weigh the alternatives. Grof

 coined the term “excellent lithium responders” for bipolar patients who enjoy long-term illness-free lives with prophylactic lithium monotherapy. 

 describes the characteristics of these patients, along with characteristics less predictive of lithium maintenance stability. Ongoing work by the International Group for the Study of Lithium-Treated Patients promises further understanding of genetic and other aspects of lithium response prediction. Lithium responsiveness may identify a diagnostic subgroup of patients with mood disorder-including some bipolar patients, as well as some unipolar patients-who have a clearly episodic, recurrent course.

 compares the maintenance benefits of lithium with those of other mood-stabilizing agents.

While patients newly confronting the reality of long-term maintenance medication may be encouraged by lithium’s benefits, they inevitably are concerned about adverse effects. The risks associated with lithium must be balanced against those of alternative medications: valproic acid derivatives and carbamazepine are associated with many potential systemic adverse effects; lamotrigine “only” has the rash risk to worry about-so to speak-but it is not effective for acute mania; and most atypical antipsychotics have a double whammy of metabolic syndrome and tardive dyskinesia. 

 compares the risks of lithium with those of alternative mood stabilizers.

Recommended maintenance serum levels with lithium are 0.5 or 0.6 to 0.8 mEq/L; some guidelines recommend levels of 0.8 to 1.0 mEq/L for breakthrough symptoms. Most guidelines recommend frequent monitoring until stable levels are confirmed in a euthymic state, then monitoring every 3 to 6 months for 12 months, and every 6 to 12 months indefinitely thereafter. Additional measurements are needed after dosage changes, introduction of factors that can alter serum levels, or in cases of relapse. Patients should be educated about lithium levels and factors that can affect them (

Lithium has a narrow therapeutic index. Clinicians must maintain vigilance for potentially serious risks and clinical manifestations of lithium toxicity. Serum levels even 25% above the upper limit of the therapeutic range (ie, 1.2 mEq/L) can cause clinical toxicity. Both magnitude and duration of exposure to a high lithium level correlate with severity of toxicity. Elderly patients may experience clinical toxicity at lower serum levels.

Overdose with serum levels in the range of 2 to 3 mEq/L can leave patients with permanent residual nephrotoxicity and neurotoxicity. Dialysis is required when serum levels are higher than 4 mEq/L and/or if the patient exhibits acute renal, CNS, or otherwise severe clinical decompensation.

 More frequent monitoring is required in situations that increase risk of lithium toxicity-particularly in the elderly-such as dehydration and drug interactions with NSAIDs, angiotensin-converting enzyme inhibitors, and thiazide diuretics.

Lithium’s well-known effects on renal function include impaired urinary concentrating capacity with polydipsia, polyuria, and nephrogenic diabetes insipidus; and nephropathy with renal functional impairment. Impaired urinary concentration capacity is common, immediate, dose-related, sometimes transient, and more frequent in women.

 It is mediated via lithium-induced glycogen synthase kinase-3Î² inhibition that leads to interference with extracellular sodium channel and aquaporin-2 water transport channel functions and the effects of antidiuretic hormone and aldosterone on primary cells of the cortical collecting duct.

 Lower serum levels, single daily dosing and, in more severe cases, adjunctive amiloride (a potassium-sparing diuretic and extracellular sodium channel blocker) may reduce impaired urinary concentration capacity. Thiazide diuretics may also help but require significant reduction of lithium doses with careful monitoring to avoid toxicity.

In up to 20% of patients receiving long-term lithium treatment, some degree of nephropathy develops.

 It begins with renal impairment (creatinine levels greater than 1.5 mg/dL) but can progress to renal failure that may require renal replacement therapy (dialysis or transplant). The absolute risks of lithium-associated renal impairment, renal failure, and/or renal replacement therapy are difficult to determine for practical reasons; however, recent research confirms the serious risk of long-term lithium use. In a meta-analysis of the adverse effects of lithium, McKnight and colleagues

 found that 0.5% of long-term lithium-treated patients were receiving renal replacement therapy, compared with 0.2% of the general population.

Results from a 2014 Swedish Renal Registry study show an incidence of 1.2% for lithium-associated renal replacement therapy.

 The patients with this worst outcome had begun lithium treatment more than 30 years previously, which suggests that more recent careful long-term monitoring and reduced maintenance lithium dosage may have protected the others. Close and colleagues

 compared bipolar patients first treated with either lithium or an alternative mood stabilizer after 1990. They found significantly higher rates of both renal impairment (10.2% vs 3.1%) and renal failure (2% vs 0.7%) in lithium-treated patients.

Other findings suggest that the incidence of nephropathy may be increasing over time.26 The researchers found 0.14 (95% confidence interval [CI], 0.06-0.22) cases of lithium-induced renal replacement therapy per million total population from 1992 through 1996 and 0.78 per million (95% CI, 0.67-0.90) from 2007 through 2011. The proportion of all renal replacement therapy cases attributed to lithium increased from 0.2% to 0.7% over that period.

Numerous caveats are important in interpreting these data.

 All 3 studies controlled for potentially confounding variables, arguing for a truly causative role of lithium. Because it is likely that the Close study underestimated the true duration of exposure, it is probable that nephropathy occurs after decades of maintenance exposure. While the hazard ratio of approximately 2.5 is concerning for severe outcomes such as nephropathy, the absolute risk difference is important: number needed for harm (NNH) for renal replacement therapy was 330, NNH for renal failure was 660 for those younger than 50, and NNH was 44 for those older than 50.

Nephropathy requires monitoring for suggestive symptoms and serum creatinine/estimated glomerular filtration rate. Patients with emerging renal impairment should undergo more in-depth assessment and must be educated about alternatives, such as lithium monotherapy at the lowest dosage with careful monitoring or use of different mood stabilizers. Lamotrigine, quetiapine, or the olanzapine-fluoxetine combination can be added to a suboptimal lithium dosage for maintenance treatment in patients with predominantly depressive recurrence risk. Divalproex, olanzapine, quetiapine, aripiprazole, or carbamazepine can be added for patients with predominantly manic/mixed episode relapse risk.

Thyroid function is more commonly affected by lithium than by other mood stabilizers. Lithium affects the thyroid axis by a number of mechanisms. Studies suggest that hypothyroidism develops in 30% of patients with BD during lithium maintenance, and up to 50% of these patients have detectable goiters by ultrasonography (compared with approximately 20% of controls).

 Women are at higher risk for hypothyroidism.

In some cases, hypothyroidism turns out to be an unmasking of autoimmune thyroiditis, which may be more common in patients with BD and unrelated to lithium exposure.

 While autoimmune thyroiditis may require referral for further evaluation and treatment, hypothyroidism is not a contraindication to lithium. It can be managed by the treating psychiatrist with supplemental levothyroxine.

Monitoring of thyroid-stimulating hormone every 3 months during the first 6 to 12 months and every 6 to 12 months (more often in women older than 45) indefinitely thereafter is recommended. Because of the importance of normal thyroid function for mood regulation, lowering the cutoff value for abnormally high thyroid-stimulating hormone from the typical 5 µIU/mL to 3 µIU/m/L is recommended.

 An important teaching point for residents is to look for hypothyroidism in patients with BD who are maintained on lithium and in whom breakthrough depression develops, because hypothyroidism is a classic cause of secondary depression. In addition, lithium-induced hyperthyroidism can cause mania.

Lithium-induced hypercalcemia and hyperparathyroidism are caused by the direct effect of lithium on parathyroid calcium sensitivity. In one study, 8.6% of lithium-treated patients with BD were found to have hyperparathyroidism.

 Recent guidelines recommend baseline and periodic calcium (but not routine parathyroid hormone) monitoring.

 Patients must also be informed that this adverse effect can include parathyroid adenomas that may require surgical removal. Fortunately, the prognosis with surgery for these benign tumors is good.

The FDA lists Brugada syndrome, a congenital cardiac arrhythmia characterized by precordial lead ST-segment elevation and risk of ventricular arrhythmia with syncope and sudden death, as a contraindication to lithium because lithium can unmask it, even at therapeutic serum levels. It may be triggered by sodium channel blockade, and thus the risk may be shared by other psychotropic agents. Patients should probably be warned about this and told to stop lithium and see a physician immediately if unexplained syncope occurs. Lithium can affect both atrial and ventricular conduc-tion, and this is of particular concern when it is prescribed in conjunction with other medications with cardiac conduction effects, or when taken in overdose.

Lithium remains FDA category D regarding safety in pregnancy because of Ebstein anomaly and other cardiovascular anomalies associated with first-trimester exposure. In the most recent teratogenicity study, first-trimester lithium exposure was associated with a 4% risk of any cardiovascular defect in the fetus, compared with 0.6% in nonteratogenic-exposed control pregnancies.35 Women who used lithium during pregnancy had a greater than 20% rate of pregnancy complications. Lithium also poses a risk to infants of breast-feeding mothers because of its high concentration in breast milk.

Another important caveat with lithium use is discontinuation risk. The affective morbidity index among 346 bipolar patients followed for up to 20 years remained stable over time, consistent with a persistent benefit of lithium in those who continue to take it.

 On the other hand, even after stable remission and gradual discontinuation, the risk of recurrence is significantly worse than in those who continue on lithium. Discontinuation also increases the risk for suicidality.

 Relapse and suicide risks are much higher with abrupt compared with gradual discontinuation. In addition, some patients may become treatment-refractory with lithium discontinuation.

Overall, lithium plays an important role in reducing morbidity and mortality associated with BD. Psychiatrists can optimize the benefits of lithium by carefully choosing patients for long-term treatment, educating patients thoroughly about risks and benefits, monitoring adverse effects and serum lithium levels regularly, and working toward minimum maintenance dosages.

Patients whose longitudinal illness pattern corresponds to the “excellent responder” profile identified by Grof should be offered lithium prophylaxis unless there are medical contraindications or poor reliability of follow-up. However, this does not mean that patients with other profiles should not be considered for lithium maintenance. Benefits may still accrue even in the absence of the characteristics of “excellent responders,” and this is something that most patients with BD (or recurrent unipolar depression) deserve to be told.

One approach is to combine modest dosages of lithium-to reduce both short-term and presumably long-term adverse effects-with other mood-stabilizing agents to ensure symptom/episode control in those for whom lithium alone is an inadequate mood stabilizer. This approach is the subject of the Lithium Treatment Moderate-Dose Use Study. In the first outcome report, at 6 months there were no significant advantages to lithium plus optimized personalized treatment, although patients in the lithium group (mean serum levels, 0.4 to 0.47 mEq/L) received 23% fewer prescriptions for atypical antipsychotics.

It may take longer to observe whether moderate-dose adjunctive lithium has clinically significant suicide prevention and neuroprotective benefits, let alone nephroprotective effects. Further data from this thoughtful work, as well as from the International Group for the Study of Lithium will help us to continue to optimize lithium use.

Perhaps my answer to the original question-whether we still use lithium-will remain a decided YES well into the future. (The patient agreed to lithium monotherapy and has done well at 18-month follow-up, managed by her family physician.)

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Dr Koek is Staff Psychiatrist at the Sepulveda Ambulatory Care Center, VA Greater Los Angeles Healthcare System; Director of the Mood Disorders Clinic, UCLA/San Fernando Psychiatry Training Program; Clinical Professor, department of psychiatry and bio-behavioral sciences at the David Geffen School of Medicine at UCLA in Los Angeles; and Teaching Faculty at the Family Medicine Residency Program, Glendale Adventist Medical Center in Glendale, Calif.

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Lithium plays an important role in reducing morbidity and mortality associated with bipolar disorder. Psychiatrists can optimize the benefits of lithium by carefully choosing patients for long-term treatment and educating them about the risks and benefits.

Ralph J. Koek, MD

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