Clinical Neuroscience

Lithium is one of the most widely used mood stabilizers and is considered a first-line treatment for bipolar disorder because of its proven antimanic and prophylactic effects.¹ This medication also can reduce the risk of suicide in patients with bipolar disorder.² However, it has a narrow therapeutic index. While lithium has many reversible adverse effects—such as tremors, gastrointestinal disturbance, and thyroid dysfunction—its perceived irreversible nephrotoxic effects makes some clinicians hesitant to prescribe it.^3,4 In this article, we describe the relationship between lithium and nephrotoxicity, explain the apparent contradiction in published research regarding this topic, and offer suggestions for how to determine whether you should continue treatment with lithium for a patient who develops renal changes.

A lithium dilemma

Many psychiatrists have faced the dilemma of whether to discontinue lithium upon the appearance of glomerular renal changes and risk exposing patients to relapse or suicide, or to continue prescribing lithium and risk development of end stage renal disease (ESRD). Discontinuing lithium is not associated with the reversal of renal changes and kidney recovery,⁵ and exposes patients to psychiatric risks, such as mood recurrence and increased risk of suicide.⁶ Switching from lithium to another mood stabilizer is associated with a host of adverse effects, including diabetes mellitus and weight gain, and mood stabilizer use is not associated with reduced renal risk in patients with bipolar disorder.⁵ For example, Markowitz et al⁶ evaluated 24 patients with renal insufficiency after an average of 13.6 years of chronic lithium treatment. Despite stopping lithium, 8 patients out of the 19 available for follow-up (42%) developed ESRD.⁶ This study also found that serum creatinine levels >2.5 mg/dL are a predictor of progression to ESRD.⁶

Discontinuing lithium is associated with high rates of mood recurrence (60% to 70%), especially for patients who had been stable on lithium for years.^7,8 If lithium is tapered slowly, the risk of mood recurrence may drop to approximately 42% over the subsequent 18 months, but this is nearly 3-fold greater than the risk of mood recurrence in patients with good response to valproate who are switched to another mood stabilizer (16.7%, c² = 4.3, P = .048),⁹ which suggests that stopping lithium is particularly problematic. Considering the lifetime consequences of bipolar illness, for most patients who have been receiving lithium for a long time, the recommendation is to continue lithium.^10,11

The reasons for conflicting evidence

Many studies indicate that there is either no statistically significant association or a very low association between lithium and developing ESRD,^12-16 while others suggest that long-term lithium treatment increases the risk of chronic nephropathy to a clinically relevant degree (note that these arguments are not mutually exclusive).^6,17-22 Much of this confusion has to do with not making a distinction between renal tubular dysfunction, which occurs early and in approximately one-half of patients treated with lithium,²³ and glomerular dysfunction, which occurs late and is associated with reductions in glomerular filtration and ESRD.²⁴ Adding to the confusion is that even without lithium, the rate of renal disease in patients with mood disorders is 2- to 3-fold higher than that of the general population.²⁵ Lithium treatment is associated with a rate that is higher still,^25-27 but this effect is erroneously exaggerated in studies that examined patients treated with lithium without comparison to a mood-disorder control group.

Renal tubular dysfunction presents as diabetes insipidus with polyuria and polydipsia, which is related to a reduced ability to concentrate the urine.²⁸ Reduced glomerular filtration rate (GFR) as a consequence of lithium treatment occurs in 15% of patients²³ and represents approximately 0.22% of patients on dialysis.¹⁸ Lithium-related reduction in GFR is a slowly progressive process that typically requires >20 years of lithium use to result in ESRD.¹⁸ While some decline in GFR may be seen within 1 year after starting lithium, the average age of patients who develop ESRD is 65 years.⁶ Interestingly, short-term animal studies have suggested that lithium may have antiproteinuric, protective, and pro-reparative effects in acute kidney injury.²⁹

Anatomical anomalies in lithium-related glomerular dysfunction

In a study conducted before improved imaging technology was developed, Markowitz et al⁶ used renal biopsy to evaluate lithium-related nephropathy in 24 patients.⁶ Findings revealed chronic tubulointerstitial nephritis in all patients, along with a wide range of abnormalities, including tubular atrophy and interstitial fibrosis interspersed with microcyst formation arising from distal tubules or collecting ducts.⁶ Focal segmental glomerulosclerosis (FSGS) was found in 50% of patients. This might have been a result of nephron loss and compensatory hypertrophy of surviving nephrons, which suggests that FSGS is possibly a post-adaptive effect (rather than a direct damaging effect) of lithium on the glomerulus. The most noticeable finding was the appearance of microcysts in 62.5% of patients.⁶ It is important to note that these biopsy techniques sampled a relatively small fraction of the kidney volume, and that microcysts might have been more prevalent.

Recently, noninvasive imaging techniques have been used to detect microcysts in patients developing lithium-related nephropathy. While ultrasound and computed tomography (CT) can detect renal microcysts, magnetic resonance imaging (MRI), specifically the half-Fourier acquisition single-shot turbo spin-echo T2-weighted and gadolinium-enhanced (FISP three-dimensional MR angiographic) sequence, is the best noninvasive technology to demonstrate the presence of renal microcysts of a diameter of 1 to 2 mm.³⁰ Ultrasound is sometimes difficult to utilize because while classic cysts appear as anechoic, lithium-induced microcysts may have the appearance of small echogenic foci.^31,32 When evaluated by CT, renal microcysts may appear as hypodense lesions.

Continue to: Recent small studies...

Recent small studies have shown that MRI can detect renal microcysts in approximately 100% of patients who are receiving chronic lithium treatment and have renal insufficiency. One MRI study found renal microcysts in all 16 patients.³³ In another MRI study of 4 patients, all were positive for renal microcysts.³⁴ The relationship between MRI findings and renal function impairment in patients receiving long-term lithium therapy is still not clear; however, 1 study that examined 35 patients who received lithium reported that the number of cysts is generally related to the duration of lithium therapy.³⁵ Thus, microcysts seem to present long before the elevation in creatinine, and nearly always present in patients with some glomerular dysfunction.

Cystic renal lesions have a wide variety of differential diagnoses, including simple renal cysts; glomerulocystic kidney disease; medullary cystic kidney disease and acquired cystic kidney disease; and multicystic dysplastic kidney and autosomal dominant polycystic kidney disease.³⁶ In patients who have a long history of lithium use, lithium-related nephrotoxicity should be added to the differential diagnosis. The ubiquitous presence of renal microcysts and their relationship to duration of lithium exposure and renal function suggest that they may be intimately related to lithium-related ESRD.³⁷

This association appears to be sufficiently reliable and clinicians can use T2-weighted MRI to determine if renal dysfunction is related to lithium. Lithium-related renal microcysts are visualized as multiple bilateral hyperintense foci with a diameter of 1 to 3 mm that involve both the cortex and medulla, tend to be symmetrically distributed throughout the kidney, and are associated with normal-sized kidneys.^33,36 Large cysts are unlikely to be related to lithium; only microcysts are associated with lithium treatment. For examples of how these cysts appear on MRI, see Figure 1, Figure 2, and Figure 3. The exact mechanism of lithium-related nephrotoxicity is unclear, but may be related to the mTOR (mammalian target of rapamycin) pathway or GSK-3beta (glycogen synthase kinase-3beta) (Box^6,37-44).

Box 1

Take-home points

In patients receiving chronic lithium treatment, it can take 20 years to produce a significant reduction in GFR. Switching patients who respond to lithium to other mood-stabilizing agents is associated with a significantly increased risk for mood recurrence and adverse consequences from the alternate medication. Because ESRD may occur more frequently in patients with mood disorders than in the general population, renal disease may be misattributed to lithium use. In approximately one-half of patients, renal disease will continue to progress after discontinuing lithium, which essentially eliminates the benefit of switching medications. This means that the decision to switch a patient who has responded well to lithium treatment for a decade or more to an alternate agent to avoid progression to ESRD may be associated with a very high potential cost but limited benefit.

One solution might be to more accurately identify patients with lithium-related glomerular disease, so that the potential benefit of switching may outweigh potential harm. The presence of renal microcysts on MRI of the kidney may be used to provide some of that reassurance. On renal biopsy, >60% of patients will have documented microcysts, and on MRI, it may approach 100%. The presence of microcysts provides potential evidence that reduced glomerular function is related to lithium. However, the absence of renal microcysts may not be as instructive—a negative MRI of the kidneys may not be sufficient evidence to rule out lithium as the culprit.

Continue to: Bottom Line

Lithium is an effective treatment for bipolar disorder, but its perceived irreversible nephrotoxic effects make some clinicians hesitant to prescribe it. Discontinuing lithium or switching to another medication also carries risks. For most patients who have been receiving lithium for a long time, the recommendation is to obtain a renal MRI and to cautiously continue lithium if the patient does not have microcysts.

Related Resources

• Hayes JF, Osborn DPJ, Francis E, et al. Prediction of individuals at high risk of chronic kidney disease during treatment with lithium for bipolar disorder. BMC Med. 2021;19(1):99. doi: 10.1186/s12916-021-01964-z
• Pelekanos M, Foo K. A resident’s guide to lithium. Current Psychiatry. 2021;20(4):e3-e7. doi:10.12788/cp.0113

Drug Brand Names

Lithium • Eskalith, Lithobid
Sirolimus • Rapamune
Valproate • Depacon

Lithium is one of the most widely used mood stabilizers and is considered a first-line treatment for bipolar disorder because of its proven antimanic and prophylactic effects.¹ This medication also can reduce the risk of suicide in patients with bipolar disorder.² However, it has a narrow therapeutic index. While lithium has many reversible adverse effects—such as tremors, gastrointestinal disturbance, and thyroid dysfunction—its perceived irreversible nephrotoxic effects makes some clinicians hesitant to prescribe it.^3,4 In this article, we describe the relationship between lithium and nephrotoxicity, explain the apparent contradiction in published research regarding this topic, and offer suggestions for how to determine whether you should continue treatment with lithium for a patient who develops renal changes.

A lithium dilemma

Many psychiatrists have faced the dilemma of whether to discontinue lithium upon the appearance of glomerular renal changes and risk exposing patients to relapse or suicide, or to continue prescribing lithium and risk development of end stage renal disease (ESRD). Discontinuing lithium is not associated with the reversal of renal changes and kidney recovery,⁵ and exposes patients to psychiatric risks, such as mood recurrence and increased risk of suicide.⁶ Switching from lithium to another mood stabilizer is associated with a host of adverse effects, including diabetes mellitus and weight gain, and mood stabilizer use is not associated with reduced renal risk in patients with bipolar disorder.⁵ For example, Markowitz et al⁶ evaluated 24 patients with renal insufficiency after an average of 13.6 years of chronic lithium treatment. Despite stopping lithium, 8 patients out of the 19 available for follow-up (42%) developed ESRD.⁶ This study also found that serum creatinine levels >2.5 mg/dL are a predictor of progression to ESRD.⁶

Discontinuing lithium is associated with high rates of mood recurrence (60% to 70%), especially for patients who had been stable on lithium for years.^7,8 If lithium is tapered slowly, the risk of mood recurrence may drop to approximately 42% over the subsequent 18 months, but this is nearly 3-fold greater than the risk of mood recurrence in patients with good response to valproate who are switched to another mood stabilizer (16.7%, c² = 4.3, P = .048),⁹ which suggests that stopping lithium is particularly problematic. Considering the lifetime consequences of bipolar illness, for most patients who have been receiving lithium for a long time, the recommendation is to continue lithium.^10,11

The reasons for conflicting evidence

Many studies indicate that there is either no statistically significant association or a very low association between lithium and developing ESRD,^12-16 while others suggest that long-term lithium treatment increases the risk of chronic nephropathy to a clinically relevant degree (note that these arguments are not mutually exclusive).^6,17-22 Much of this confusion has to do with not making a distinction between renal tubular dysfunction, which occurs early and in approximately one-half of patients treated with lithium,²³ and glomerular dysfunction, which occurs late and is associated with reductions in glomerular filtration and ESRD.²⁴ Adding to the confusion is that even without lithium, the rate of renal disease in patients with mood disorders is 2- to 3-fold higher than that of the general population.²⁵ Lithium treatment is associated with a rate that is higher still,^25-27 but this effect is erroneously exaggerated in studies that examined patients treated with lithium without comparison to a mood-disorder control group.

Renal tubular dysfunction presents as diabetes insipidus with polyuria and polydipsia, which is related to a reduced ability to concentrate the urine.²⁸ Reduced glomerular filtration rate (GFR) as a consequence of lithium treatment occurs in 15% of patients²³ and represents approximately 0.22% of patients on dialysis.¹⁸ Lithium-related reduction in GFR is a slowly progressive process that typically requires >20 years of lithium use to result in ESRD.¹⁸ While some decline in GFR may be seen within 1 year after starting lithium, the average age of patients who develop ESRD is 65 years.⁶ Interestingly, short-term animal studies have suggested that lithium may have antiproteinuric, protective, and pro-reparative effects in acute kidney injury.²⁹

Anatomical anomalies in lithium-related glomerular dysfunction

In a study conducted before improved imaging technology was developed, Markowitz et al⁶ used renal biopsy to evaluate lithium-related nephropathy in 24 patients.⁶ Findings revealed chronic tubulointerstitial nephritis in all patients, along with a wide range of abnormalities, including tubular atrophy and interstitial fibrosis interspersed with microcyst formation arising from distal tubules or collecting ducts.⁶ Focal segmental glomerulosclerosis (FSGS) was found in 50% of patients. This might have been a result of nephron loss and compensatory hypertrophy of surviving nephrons, which suggests that FSGS is possibly a post-adaptive effect (rather than a direct damaging effect) of lithium on the glomerulus. The most noticeable finding was the appearance of microcysts in 62.5% of patients.⁶ It is important to note that these biopsy techniques sampled a relatively small fraction of the kidney volume, and that microcysts might have been more prevalent.

Recently, noninvasive imaging techniques have been used to detect microcysts in patients developing lithium-related nephropathy. While ultrasound and computed tomography (CT) can detect renal microcysts, magnetic resonance imaging (MRI), specifically the half-Fourier acquisition single-shot turbo spin-echo T2-weighted and gadolinium-enhanced (FISP three-dimensional MR angiographic) sequence, is the best noninvasive technology to demonstrate the presence of renal microcysts of a diameter of 1 to 2 mm.³⁰ Ultrasound is sometimes difficult to utilize because while classic cysts appear as anechoic, lithium-induced microcysts may have the appearance of small echogenic foci.^31,32 When evaluated by CT, renal microcysts may appear as hypodense lesions.

Continue to: Recent small studies...

Recent small studies have shown that MRI can detect renal microcysts in approximately 100% of patients who are receiving chronic lithium treatment and have renal insufficiency. One MRI study found renal microcysts in all 16 patients.³³ In another MRI study of 4 patients, all were positive for renal microcysts.³⁴ The relationship between MRI findings and renal function impairment in patients receiving long-term lithium therapy is still not clear; however, 1 study that examined 35 patients who received lithium reported that the number of cysts is generally related to the duration of lithium therapy.³⁵ Thus, microcysts seem to present long before the elevation in creatinine, and nearly always present in patients with some glomerular dysfunction.

Cystic renal lesions have a wide variety of differential diagnoses, including simple renal cysts; glomerulocystic kidney disease; medullary cystic kidney disease and acquired cystic kidney disease; and multicystic dysplastic kidney and autosomal dominant polycystic kidney disease.³⁶ In patients who have a long history of lithium use, lithium-related nephrotoxicity should be added to the differential diagnosis. The ubiquitous presence of renal microcysts and their relationship to duration of lithium exposure and renal function suggest that they may be intimately related to lithium-related ESRD.³⁷

This association appears to be sufficiently reliable and clinicians can use T2-weighted MRI to determine if renal dysfunction is related to lithium. Lithium-related renal microcysts are visualized as multiple bilateral hyperintense foci with a diameter of 1 to 3 mm that involve both the cortex and medulla, tend to be symmetrically distributed throughout the kidney, and are associated with normal-sized kidneys.^33,36 Large cysts are unlikely to be related to lithium; only microcysts are associated with lithium treatment. For examples of how these cysts appear on MRI, see Figure 1, Figure 2, and Figure 3. The exact mechanism of lithium-related nephrotoxicity is unclear, but may be related to the mTOR (mammalian target of rapamycin) pathway or GSK-3beta (glycogen synthase kinase-3beta) (Box^6,37-44).

Box 1

Take-home points

In patients receiving chronic lithium treatment, it can take 20 years to produce a significant reduction in GFR. Switching patients who respond to lithium to other mood-stabilizing agents is associated with a significantly increased risk for mood recurrence and adverse consequences from the alternate medication. Because ESRD may occur more frequently in patients with mood disorders than in the general population, renal disease may be misattributed to lithium use. In approximately one-half of patients, renal disease will continue to progress after discontinuing lithium, which essentially eliminates the benefit of switching medications. This means that the decision to switch a patient who has responded well to lithium treatment for a decade or more to an alternate agent to avoid progression to ESRD may be associated with a very high potential cost but limited benefit.

One solution might be to more accurately identify patients with lithium-related glomerular disease, so that the potential benefit of switching may outweigh potential harm. The presence of renal microcysts on MRI of the kidney may be used to provide some of that reassurance. On renal biopsy, >60% of patients will have documented microcysts, and on MRI, it may approach 100%. The presence of microcysts provides potential evidence that reduced glomerular function is related to lithium. However, the absence of renal microcysts may not be as instructive—a negative MRI of the kidneys may not be sufficient evidence to rule out lithium as the culprit.

Continue to: Bottom Line

Lithium is an effective treatment for bipolar disorder, but its perceived irreversible nephrotoxic effects make some clinicians hesitant to prescribe it. Discontinuing lithium or switching to another medication also carries risks. For most patients who have been receiving lithium for a long time, the recommendation is to obtain a renal MRI and to cautiously continue lithium if the patient does not have microcysts.

Related Resources

• Hayes JF, Osborn DPJ, Francis E, et al. Prediction of individuals at high risk of chronic kidney disease during treatment with lithium for bipolar disorder. BMC Med. 2021;19(1):99. doi: 10.1186/s12916-021-01964-z
• Pelekanos M, Foo K. A resident’s guide to lithium. Current Psychiatry. 2021;20(4):e3-e7. doi:10.12788/cp.0113

Drug Brand Names

Lithium • Eskalith, Lithobid
Sirolimus • Rapamune
Valproate • Depacon

Lithium is one of the most widely used mood stabilizers and is considered a first-line treatment for bipolar disorder because of its proven antimanic and prophylactic effects.¹ This medication also can reduce the risk of suicide in patients with bipolar disorder.² However, it has a narrow therapeutic index. While lithium has many reversible adverse effects—such as tremors, gastrointestinal disturbance, and thyroid dysfunction—its perceived irreversible nephrotoxic effects makes some clinicians hesitant to prescribe it.^3,4 In this article, we describe the relationship between lithium and nephrotoxicity, explain the apparent contradiction in published research regarding this topic, and offer suggestions for how to determine whether you should continue treatment with lithium for a patient who develops renal changes.

A lithium dilemma

Many psychiatrists have faced the dilemma of whether to discontinue lithium upon the appearance of glomerular renal changes and risk exposing patients to relapse or suicide, or to continue prescribing lithium and risk development of end stage renal disease (ESRD). Discontinuing lithium is not associated with the reversal of renal changes and kidney recovery,⁵ and exposes patients to psychiatric risks, such as mood recurrence and increased risk of suicide.⁶ Switching from lithium to another mood stabilizer is associated with a host of adverse effects, including diabetes mellitus and weight gain, and mood stabilizer use is not associated with reduced renal risk in patients with bipolar disorder.⁵ For example, Markowitz et al⁶ evaluated 24 patients with renal insufficiency after an average of 13.6 years of chronic lithium treatment. Despite stopping lithium, 8 patients out of the 19 available for follow-up (42%) developed ESRD.⁶ This study also found that serum creatinine levels >2.5 mg/dL are a predictor of progression to ESRD.⁶

Discontinuing lithium is associated with high rates of mood recurrence (60% to 70%), especially for patients who had been stable on lithium for years.^7,8 If lithium is tapered slowly, the risk of mood recurrence may drop to approximately 42% over the subsequent 18 months, but this is nearly 3-fold greater than the risk of mood recurrence in patients with good response to valproate who are switched to another mood stabilizer (16.7%, c² = 4.3, P = .048),⁹ which suggests that stopping lithium is particularly problematic. Considering the lifetime consequences of bipolar illness, for most patients who have been receiving lithium for a long time, the recommendation is to continue lithium.^10,11

The reasons for conflicting evidence

Many studies indicate that there is either no statistically significant association or a very low association between lithium and developing ESRD,^12-16 while others suggest that long-term lithium treatment increases the risk of chronic nephropathy to a clinically relevant degree (note that these arguments are not mutually exclusive).^6,17-22 Much of this confusion has to do with not making a distinction between renal tubular dysfunction, which occurs early and in approximately one-half of patients treated with lithium,²³ and glomerular dysfunction, which occurs late and is associated with reductions in glomerular filtration and ESRD.²⁴ Adding to the confusion is that even without lithium, the rate of renal disease in patients with mood disorders is 2- to 3-fold higher than that of the general population.²⁵ Lithium treatment is associated with a rate that is higher still,^25-27 but this effect is erroneously exaggerated in studies that examined patients treated with lithium without comparison to a mood-disorder control group.

Renal tubular dysfunction presents as diabetes insipidus with polyuria and polydipsia, which is related to a reduced ability to concentrate the urine.²⁸ Reduced glomerular filtration rate (GFR) as a consequence of lithium treatment occurs in 15% of patients²³ and represents approximately 0.22% of patients on dialysis.¹⁸ Lithium-related reduction in GFR is a slowly progressive process that typically requires >20 years of lithium use to result in ESRD.¹⁸ While some decline in GFR may be seen within 1 year after starting lithium, the average age of patients who develop ESRD is 65 years.⁶ Interestingly, short-term animal studies have suggested that lithium may have antiproteinuric, protective, and pro-reparative effects in acute kidney injury.²⁹

Anatomical anomalies in lithium-related glomerular dysfunction

In a study conducted before improved imaging technology was developed, Markowitz et al⁶ used renal biopsy to evaluate lithium-related nephropathy in 24 patients.⁶ Findings revealed chronic tubulointerstitial nephritis in all patients, along with a wide range of abnormalities, including tubular atrophy and interstitial fibrosis interspersed with microcyst formation arising from distal tubules or collecting ducts.⁶ Focal segmental glomerulosclerosis (FSGS) was found in 50% of patients. This might have been a result of nephron loss and compensatory hypertrophy of surviving nephrons, which suggests that FSGS is possibly a post-adaptive effect (rather than a direct damaging effect) of lithium on the glomerulus. The most noticeable finding was the appearance of microcysts in 62.5% of patients.⁶ It is important to note that these biopsy techniques sampled a relatively small fraction of the kidney volume, and that microcysts might have been more prevalent.

Recently, noninvasive imaging techniques have been used to detect microcysts in patients developing lithium-related nephropathy. While ultrasound and computed tomography (CT) can detect renal microcysts, magnetic resonance imaging (MRI), specifically the half-Fourier acquisition single-shot turbo spin-echo T2-weighted and gadolinium-enhanced (FISP three-dimensional MR angiographic) sequence, is the best noninvasive technology to demonstrate the presence of renal microcysts of a diameter of 1 to 2 mm.³⁰ Ultrasound is sometimes difficult to utilize because while classic cysts appear as anechoic, lithium-induced microcysts may have the appearance of small echogenic foci.^31,32 When evaluated by CT, renal microcysts may appear as hypodense lesions.

Continue to: Recent small studies...

Recent small studies have shown that MRI can detect renal microcysts in approximately 100% of patients who are receiving chronic lithium treatment and have renal insufficiency. One MRI study found renal microcysts in all 16 patients.³³ In another MRI study of 4 patients, all were positive for renal microcysts.³⁴ The relationship between MRI findings and renal function impairment in patients receiving long-term lithium therapy is still not clear; however, 1 study that examined 35 patients who received lithium reported that the number of cysts is generally related to the duration of lithium therapy.³⁵ Thus, microcysts seem to present long before the elevation in creatinine, and nearly always present in patients with some glomerular dysfunction.

Cystic renal lesions have a wide variety of differential diagnoses, including simple renal cysts; glomerulocystic kidney disease; medullary cystic kidney disease and acquired cystic kidney disease; and multicystic dysplastic kidney and autosomal dominant polycystic kidney disease.³⁶ In patients who have a long history of lithium use, lithium-related nephrotoxicity should be added to the differential diagnosis. The ubiquitous presence of renal microcysts and their relationship to duration of lithium exposure and renal function suggest that they may be intimately related to lithium-related ESRD.³⁷

This association appears to be sufficiently reliable and clinicians can use T2-weighted MRI to determine if renal dysfunction is related to lithium. Lithium-related renal microcysts are visualized as multiple bilateral hyperintense foci with a diameter of 1 to 3 mm that involve both the cortex and medulla, tend to be symmetrically distributed throughout the kidney, and are associated with normal-sized kidneys.^33,36 Large cysts are unlikely to be related to lithium; only microcysts are associated with lithium treatment. For examples of how these cysts appear on MRI, see Figure 1, Figure 2, and Figure 3. The exact mechanism of lithium-related nephrotoxicity is unclear, but may be related to the mTOR (mammalian target of rapamycin) pathway or GSK-3beta (glycogen synthase kinase-3beta) (Box^6,37-44).

Box 1

Take-home points

In patients receiving chronic lithium treatment, it can take 20 years to produce a significant reduction in GFR. Switching patients who respond to lithium to other mood-stabilizing agents is associated with a significantly increased risk for mood recurrence and adverse consequences from the alternate medication. Because ESRD may occur more frequently in patients with mood disorders than in the general population, renal disease may be misattributed to lithium use. In approximately one-half of patients, renal disease will continue to progress after discontinuing lithium, which essentially eliminates the benefit of switching medications. This means that the decision to switch a patient who has responded well to lithium treatment for a decade or more to an alternate agent to avoid progression to ESRD may be associated with a very high potential cost but limited benefit.

One solution might be to more accurately identify patients with lithium-related glomerular disease, so that the potential benefit of switching may outweigh potential harm. The presence of renal microcysts on MRI of the kidney may be used to provide some of that reassurance. On renal biopsy, >60% of patients will have documented microcysts, and on MRI, it may approach 100%. The presence of microcysts provides potential evidence that reduced glomerular function is related to lithium. However, the absence of renal microcysts may not be as instructive—a negative MRI of the kidneys may not be sufficient evidence to rule out lithium as the culprit.

Continue to: Bottom Line

Lithium is an effective treatment for bipolar disorder, but its perceived irreversible nephrotoxic effects make some clinicians hesitant to prescribe it. Discontinuing lithium or switching to another medication also carries risks. For most patients who have been receiving lithium for a long time, the recommendation is to obtain a renal MRI and to cautiously continue lithium if the patient does not have microcysts.

Related Resources

• Hayes JF, Osborn DPJ, Francis E, et al. Prediction of individuals at high risk of chronic kidney disease during treatment with lithium for bipolar disorder. BMC Med. 2021;19(1):99. doi: 10.1186/s12916-021-01964-z
• Pelekanos M, Foo K. A resident’s guide to lithium. Current Psychiatry. 2021;20(4):e3-e7. doi:10.12788/cp.0113

Drug Brand Names

Lithium • Eskalith, Lithobid
Sirolimus • Rapamune
Valproate • Depacon

Posttraumatic stress disorder (PTSD) occurs acutely and chronically in the aftermath of severe and potentially life-threatening trauma.¹ The prevalence of PTSD varies significantly across countries and by type of trauma (Box^1-7).

Box

Individuals who develop PTSD experience a wide range of symptoms.⁸ These can be categorized as PTSD-specific symptoms, or nonspecific symptoms. PTSD-specific symptoms include nightmares, flashbacks, dissociative reactions, hyperreactivity or hyperarousal, distress with reminders of trauma, and avoidance of trauma-related physical reminders and thoughts/feelings (Table⁸). Nonspecific symptoms include depressive and anxiety symptoms and significant problems in social, relationship, or work situations.⁸

While successful treatment necessitates taking all of these symptoms into account, understanding the pathophysiology of PTSD can inform a more focused and ration­al treatment approach. In this article, we describe some key pathophysiologic PTSD studies, and focus on PTSD-specific psychopathology to inform treatment.

Brain systems implicated in PTSD

Neuropeptide Y (NPY) is an anxiolytic endogenous peptide that has connections to the hypothalamic-pituitary-adrenal (HPA) axis. Its levels can be modulated by stress.⁹ Preclinical and clinical studies strongly support a potential role of NPY dysfunction in the pathophysiology of PTSD. Lower concentrations of NPY increase susceptibility to PTSD in combat veterans¹⁰ and in animal models.¹¹ Three single-nucleotide polymorphisms (SNPs) appear to mediate this effect.¹² These findings strongly support pharmaceutical targeting this system as a useful therapeutic approach.^13,14 Indeed, intranasal NPY administered as a single dose reduces anxiety in animal models¹⁵ and in humans,¹⁶ but this work has not yet translated into clinical tools.

Corticotropin-releasing hormone receptor (CRHR1) gene. Corticotropin-releasing hormone has been implicated in PTSD.¹⁷ Corticotropin-releasing hormone receptors (CRHR) are important mediators in response to stress.^18,19 They bind corticotropin-releasing hormone and contribute to the integration of autonomic, behavioral, and immune responses to stress.²⁰ Single-nucleotide polymorphisms in the regulatory portion of the CRHR1 gene are associated with an increased risk for depression in adults who have a history of child abuse.²¹

The CRHR1 receptor antagonist GSK561679 is an investigational agent for the treatment of mood and anxiety disorders.²² In exploratory studies,^23,24 GSK561679 was found to inhibit fear-potentiated startle in patients with PTSD, but not overall PTSD symptoms, although a subset of women with a specific genetic variant of the CRHR1 gene (rs110402) experienced significant benefit.^25,26 This suggests that we must learn more about this system before we proceed.²⁷

Brain-derived neurotrophic factor (BDNF). The synthesis of BDNF is influenced by neuronal activity in the brain and plays a role in synaptic transmission and plasticity.²⁸ Brain-derived neuro­trophic factor is encoded by the BDNF gene, which has been implicated in stress vulnerability.²⁹ A common SNP in the pro-region of the human BDNF gene results in a valine-to-methionine substitution at the 66th amino acid (Val66Met). The functional Val66Met polymorphism may have a role in the risk of developing PTSD. However, not all studies support this finding. One study found that an SNP with a resulting Val66Met polymorphism is associated with adult PTSD symptoms after childhood abuse, while a meta-analysis of 7 studies did not confirm this.^30,31 We need to learn more about BDNF before we proceed.³²

Continue to: Serotonin transporter (5-HTT) gene

Serotonin transporter (5-HTT) gene. Serotonin transporter is a monoamine transporter protein that terminates the neurotransmitter signal by transporting serotonin from the synaptic cleft back into the presynaptic neuron. It is encoded by the SLC6A4 gene, which resides on the long arm of chromosome 17(17q11.1-q12). It is a large gene with 31 kilo bases and 14 separate exons (transcribed regions).^33,34

This gene has several variants. The best-studied is a variation in the promoter region. A 44-bp insertion or deletion yields the “long” and “short” alleles, respectively. The proteins produced by the 2 alleles are identical, but the amount of expressed protein is different. The short allele (“S”) is associated with a nearly 50% reduction in 5-HTT expression in both homozygotes and heterozygotes.³⁵ A greater incidence of serotonin transporter promoter region (5-HTTLPR) S has been found in individuals with PTSD compared with those without PTSD,^36-38 and 5-HTTLPR S increases the risk of PTSD in individuals with low social support³⁹ or after very few traumatic events.⁴⁰ The short allele variant is also associated with depression in individuals who face adversity.^35,41

The overrepresentation of the short form of 5-HTTLPR in individuals who develop PTSD may represent a potential problem with current treatment paradigms, in which an antidepressant is the first-line treatment, because this allele is associated with reduced response to antidepressants.^42,43 More distressing is the possible association of this allele with increased suicide risk, particularly violent suicide⁴⁴ or repeated suicide attempts.⁴⁵

Furthermore, a functional MRI study of patients who were anxious revealed that in individuals with the short allele, administration of citalopram was associated with increased amygdala activity in response to negative stimuli, and reduced activity in response to positive stimuli.⁴⁶ This suggests that antidepressant treatment may actually worsen fear response in patients with PTSD. Clearly, additional research is needed to determine if having the SLC6A4 gene alters clinical outcomes in response to an antidepressant in a patient with PTSD. In the meantime, clinicians should use vigilance and a critical mindset when they administer antidepressants to a patient who has PTSD.

Catechol-o-methyltransferase (COMT) is one of the enzymes that degrades catecholamines such as dopamine, epinephrine, and norepinephrine (NE).⁴⁷ In humans, COMT protein is encoded by the COMT gene. This gene is associated with allelic variants; the best-studied of these is Val158Met. COMT Val158Met polymorphism (rs4860) has been linked to deficits in stress response and emotional resilience.^48,49 Val158Met is associated with a 40% reduction in enzyme activity and slower catalysis of catecholamines, resulting in increases in catecholamines levels in the brain, which may increase the risk of developing PTSD.⁵⁰ Individuals homozygous for this SNP (Met/Met) are highly susceptible to develop PTSD independently of the severity of the trauma they experienced.⁵¹ The Val158Met polymorphism may be associated with other abnormalities, such as cognitive problems with specific frontal cortical activity, and also with improved antidepressant response (valine homozygotes less responsive than methionine homozygotes).⁵² This gene is available on gene testing profiles.

Continue to: The role of norepinephrine in PTSD

The role of norepinephrine in PTSD

Perhaps the greatest advance in the understanding of the pathophysiology of PTSD relates to changes in brain NE. The HPA axis is responsible for coordinating the hormonal response to stress. Dysregulation of this axis and increased activity of the central and peripheral noradrenergic systems are usually observed in patients with PTSD.⁵³ Several monoamine neurotransmitters are important in the regulation and function of the HPA axis. Norepinephrine plays a major role in stress.

The clinical PTSD-specific criteria are all descriptions of excessive noradrenergic tone.⁵⁴ For example, hypervigilance and hyperstartle are clearly anticipated as evidence of NE stimulation. Flashbacks, particularly those that might be precipitated by environmental cues, also can be a manifestation of the vigilance induced by NE. Sleep disturbances (insomnia and nightmares) are present; insomnia is reported more often than nightmares.⁵⁵ Increased catecholamine levels, particularly NE, are a feature of sleep disturbances associated with middle insomnia. Dreams can be remembered only if you wake up during dreaming. Catecholamines do not change the content of dreams, just recall.⁵⁶

In a study of central noradrenergic tone in patients with PTSD, 6 hourly CSF samples were collected from 11 male combat veterans with PTSD and 8 healthy controls.⁵⁷ Participants with PTSD had significantly higher CSF NE concentrations (0.55 ± 0.17 pmol/ml vs 0.39 ± 0.16 pmol/mL in the PTSD and control groups, respectively; F = 4.49, P < .05).⁵⁷ Overall PTSD symptoms correlated significantly with CSF NE levels (r = 0.82, P <.005), and PTSD-specific symptoms such as avoidance (r = 0.79, P = .004). Intrusive thoughts (r = 0.57, P = .07) and hyperarousal (r = 0.54, P = .09) were also related.⁵⁷ This relationship is unique; patients with PTSD with predominant depressive symptoms do not have elevated plasma NE levels.⁵⁸

In the human brain, there are 3 main groups of NE receptors: alpha-1 receptors, alpha-2 receptors, and beta receptors.⁵⁹ Alpha-1 receptors (alpha-1A, alpha-1B, and alpha-1D) are postsynaptic and mediate increase in inositol trisphosphate (IP₃) and intracellular calcium (Ca²⁺). Alpha-2 receptors (alpha-2A, alpha-2B, alpha-2C) in the CNS are presynaptic autoreceptors and serve to reduce NE release. Beta receptors (beta-1, beta-2, beta-3) inhibit cyclic adenosine monophosphate (cAMP) production.⁵⁹ The effects of inhibition of alpha or beta receptors are different. Inhibition of beta receptors is associated with depressive symptoms and depressive syndrome, inhibition of peripheral beta receptors is associated with reductions in anxiety (generally reduction of pulse, sweating, tremor),⁶⁰ and inhibition of central alpha-1 receptors is associated with reduced PTSD symptoms.⁶¹

Choice of agents for PTSD-specific symptoms

As outlined in the Table,⁸ PTSD is characterized by 3 types of symptoms that are specific for PTSD. Trauma-focused psychotherapy^62,63 and selective serotonin reuptake inhibitors (SSRIs)⁶⁴ are considered first-line therapy for PTSD. Only sertraline and paroxetine are FDA-approved for treating PTSD. However, the effect size for SSRIs is quite small; improvement is only 23% to 30% greater than placebo.^64,65 Furthermore, studies have shown that these medications have little effect on insomnia, hyperarousal, or other PTSD-specific symptoms.^66,67 Studies examining military veterans with PTSD have found that these patients tend to have little or no response to antidepressants.^68,69

Continue to: Serotonin transporter promoter...

Serotonin transporter promoter region gene short-type variants, which possibly increase an individual’s predisposition to developing PTSD, may explain the abundance of depressive symptoms in this condition and the subdued response to antidepressants. Specifically, an anticipated preponderance of these alleles may be associated with poorer outcomes. Non-SSRI treatments, such as low-dose aripiprazole, may be alternatives,⁷⁰ but these approaches have not been adequately developed.

On the other hand, animal models support antagonism of the postsynaptic alpha-1 adrenergic receptor of the CNS as a target for PTSD treatment.⁷¹ Although prazosin is not currently FDA-approved for treating PTSD, in placebo-controlled studies, nightmares and PTSD total symptoms improved with prazosin, and evidence suggests that it should be used 2 or 3 times a day for all PTSD symptoms.⁶¹ Prazosin may be helpful for treating sleep problems commonly experienced by people with PTSD. Blockade of histamine will also improve sleep disturbance and reduce nightmares, but it may not be as effective as prazosin.⁷²

Quetiapine might be another non-SSRI option for treating patients with PTSD. It is an antagonist with high affinity tothehistamine-1 receptor at low doses. Norquetiapine is an alpha-2 antagonist that increases brain NE levels. Both quetiapine and norquetiapine are alpha-1 antagonists. There is no beta blockade and no SSRI effect, but some 5HT2A blockade, which may be anxiolytic. Compared with placebo, an average quetiapine dose of 258 mg/d resulted in significantly greater reductions in Clinician-Administered PTSD Scale total score, re-experiencing score, and hyperarousal score.⁷³

Unfortunately, none of the non-SSRI options have been adequately evaluated. For now, clinicians need to continue to use SSRIs, and researchers need to continue to explore mechanism-guided alternatives.

Bottom Line

Understanding the mechanisms of the pathophysiology of posttraumatic stress disorder (PTSD) may allow clinicians to “jump ahead” of clinical studies and FDA indications. Clinicians may reasonably use alpha-1 antagonists (eg, prazosin, quetiapine) for general clinical improvement of patients with PTSD, particularly for PTSD-specific symptoms. Using antihistamines to reduce anxiety (especially in patients who have the COMT Val158Met polymorphism) may also be reasonable.

Related Resources

• North CS, Hong BA, Downs DL. PTSD: a systematic approach to diagnosis and treatment. Current Psychiatry. 2018;17(4):35-43.
• Zhang Y, Ren R, Sanford LD, et al. The effects of prazosin on sleep disturbances in post-traumatic stress disorder: a systematic review and meta-analysis. Sleep Med. 2019; 67:225-231.

Drug Brand Names

Aripiprazole • Abilify
Citalopram • Celexa
Paroxetine • Paxil
Prazosin • Minipress
Quetiapine • Seroquel
Sertraline • Zoloft

Posttraumatic stress disorder (PTSD) occurs acutely and chronically in the aftermath of severe and potentially life-threatening trauma.¹ The prevalence of PTSD varies significantly across countries and by type of trauma (Box^1-7).

Box

Individuals who develop PTSD experience a wide range of symptoms.⁸ These can be categorized as PTSD-specific symptoms, or nonspecific symptoms. PTSD-specific symptoms include nightmares, flashbacks, dissociative reactions, hyperreactivity or hyperarousal, distress with reminders of trauma, and avoidance of trauma-related physical reminders and thoughts/feelings (Table⁸). Nonspecific symptoms include depressive and anxiety symptoms and significant problems in social, relationship, or work situations.⁸

While successful treatment necessitates taking all of these symptoms into account, understanding the pathophysiology of PTSD can inform a more focused and ration­al treatment approach. In this article, we describe some key pathophysiologic PTSD studies, and focus on PTSD-specific psychopathology to inform treatment.

Brain systems implicated in PTSD

Neuropeptide Y (NPY) is an anxiolytic endogenous peptide that has connections to the hypothalamic-pituitary-adrenal (HPA) axis. Its levels can be modulated by stress.⁹ Preclinical and clinical studies strongly support a potential role of NPY dysfunction in the pathophysiology of PTSD. Lower concentrations of NPY increase susceptibility to PTSD in combat veterans¹⁰ and in animal models.¹¹ Three single-nucleotide polymorphisms (SNPs) appear to mediate this effect.¹² These findings strongly support pharmaceutical targeting this system as a useful therapeutic approach.^13,14 Indeed, intranasal NPY administered as a single dose reduces anxiety in animal models¹⁵ and in humans,¹⁶ but this work has not yet translated into clinical tools.

Corticotropin-releasing hormone receptor (CRHR1) gene. Corticotropin-releasing hormone has been implicated in PTSD.¹⁷ Corticotropin-releasing hormone receptors (CRHR) are important mediators in response to stress.^18,19 They bind corticotropin-releasing hormone and contribute to the integration of autonomic, behavioral, and immune responses to stress.²⁰ Single-nucleotide polymorphisms in the regulatory portion of the CRHR1 gene are associated with an increased risk for depression in adults who have a history of child abuse.²¹

The CRHR1 receptor antagonist GSK561679 is an investigational agent for the treatment of mood and anxiety disorders.²² In exploratory studies,^23,24 GSK561679 was found to inhibit fear-potentiated startle in patients with PTSD, but not overall PTSD symptoms, although a subset of women with a specific genetic variant of the CRHR1 gene (rs110402) experienced significant benefit.^25,26 This suggests that we must learn more about this system before we proceed.²⁷

Brain-derived neurotrophic factor (BDNF). The synthesis of BDNF is influenced by neuronal activity in the brain and plays a role in synaptic transmission and plasticity.²⁸ Brain-derived neuro­trophic factor is encoded by the BDNF gene, which has been implicated in stress vulnerability.²⁹ A common SNP in the pro-region of the human BDNF gene results in a valine-to-methionine substitution at the 66th amino acid (Val66Met). The functional Val66Met polymorphism may have a role in the risk of developing PTSD. However, not all studies support this finding. One study found that an SNP with a resulting Val66Met polymorphism is associated with adult PTSD symptoms after childhood abuse, while a meta-analysis of 7 studies did not confirm this.^30,31 We need to learn more about BDNF before we proceed.³²

Continue to: Serotonin transporter (5-HTT) gene

Serotonin transporter (5-HTT) gene. Serotonin transporter is a monoamine transporter protein that terminates the neurotransmitter signal by transporting serotonin from the synaptic cleft back into the presynaptic neuron. It is encoded by the SLC6A4 gene, which resides on the long arm of chromosome 17(17q11.1-q12). It is a large gene with 31 kilo bases and 14 separate exons (transcribed regions).^33,34

This gene has several variants. The best-studied is a variation in the promoter region. A 44-bp insertion or deletion yields the “long” and “short” alleles, respectively. The proteins produced by the 2 alleles are identical, but the amount of expressed protein is different. The short allele (“S”) is associated with a nearly 50% reduction in 5-HTT expression in both homozygotes and heterozygotes.³⁵ A greater incidence of serotonin transporter promoter region (5-HTTLPR) S has been found in individuals with PTSD compared with those without PTSD,^36-38 and 5-HTTLPR S increases the risk of PTSD in individuals with low social support³⁹ or after very few traumatic events.⁴⁰ The short allele variant is also associated with depression in individuals who face adversity.^35,41

The overrepresentation of the short form of 5-HTTLPR in individuals who develop PTSD may represent a potential problem with current treatment paradigms, in which an antidepressant is the first-line treatment, because this allele is associated with reduced response to antidepressants.^42,43 More distressing is the possible association of this allele with increased suicide risk, particularly violent suicide⁴⁴ or repeated suicide attempts.⁴⁵

Furthermore, a functional MRI study of patients who were anxious revealed that in individuals with the short allele, administration of citalopram was associated with increased amygdala activity in response to negative stimuli, and reduced activity in response to positive stimuli.⁴⁶ This suggests that antidepressant treatment may actually worsen fear response in patients with PTSD. Clearly, additional research is needed to determine if having the SLC6A4 gene alters clinical outcomes in response to an antidepressant in a patient with PTSD. In the meantime, clinicians should use vigilance and a critical mindset when they administer antidepressants to a patient who has PTSD.

Catechol-o-methyltransferase (COMT) is one of the enzymes that degrades catecholamines such as dopamine, epinephrine, and norepinephrine (NE).⁴⁷ In humans, COMT protein is encoded by the COMT gene. This gene is associated with allelic variants; the best-studied of these is Val158Met. COMT Val158Met polymorphism (rs4860) has been linked to deficits in stress response and emotional resilience.^48,49 Val158Met is associated with a 40% reduction in enzyme activity and slower catalysis of catecholamines, resulting in increases in catecholamines levels in the brain, which may increase the risk of developing PTSD.⁵⁰ Individuals homozygous for this SNP (Met/Met) are highly susceptible to develop PTSD independently of the severity of the trauma they experienced.⁵¹ The Val158Met polymorphism may be associated with other abnormalities, such as cognitive problems with specific frontal cortical activity, and also with improved antidepressant response (valine homozygotes less responsive than methionine homozygotes).⁵² This gene is available on gene testing profiles.

Continue to: The role of norepinephrine in PTSD

The role of norepinephrine in PTSD

Perhaps the greatest advance in the understanding of the pathophysiology of PTSD relates to changes in brain NE. The HPA axis is responsible for coordinating the hormonal response to stress. Dysregulation of this axis and increased activity of the central and peripheral noradrenergic systems are usually observed in patients with PTSD.⁵³ Several monoamine neurotransmitters are important in the regulation and function of the HPA axis. Norepinephrine plays a major role in stress.

The clinical PTSD-specific criteria are all descriptions of excessive noradrenergic tone.⁵⁴ For example, hypervigilance and hyperstartle are clearly anticipated as evidence of NE stimulation. Flashbacks, particularly those that might be precipitated by environmental cues, also can be a manifestation of the vigilance induced by NE. Sleep disturbances (insomnia and nightmares) are present; insomnia is reported more often than nightmares.⁵⁵ Increased catecholamine levels, particularly NE, are a feature of sleep disturbances associated with middle insomnia. Dreams can be remembered only if you wake up during dreaming. Catecholamines do not change the content of dreams, just recall.⁵⁶

In a study of central noradrenergic tone in patients with PTSD, 6 hourly CSF samples were collected from 11 male combat veterans with PTSD and 8 healthy controls.⁵⁷ Participants with PTSD had significantly higher CSF NE concentrations (0.55 ± 0.17 pmol/ml vs 0.39 ± 0.16 pmol/mL in the PTSD and control groups, respectively; F = 4.49, P < .05).⁵⁷ Overall PTSD symptoms correlated significantly with CSF NE levels (r = 0.82, P <.005), and PTSD-specific symptoms such as avoidance (r = 0.79, P = .004). Intrusive thoughts (r = 0.57, P = .07) and hyperarousal (r = 0.54, P = .09) were also related.⁵⁷ This relationship is unique; patients with PTSD with predominant depressive symptoms do not have elevated plasma NE levels.⁵⁸

In the human brain, there are 3 main groups of NE receptors: alpha-1 receptors, alpha-2 receptors, and beta receptors.⁵⁹ Alpha-1 receptors (alpha-1A, alpha-1B, and alpha-1D) are postsynaptic and mediate increase in inositol trisphosphate (IP₃) and intracellular calcium (Ca²⁺). Alpha-2 receptors (alpha-2A, alpha-2B, alpha-2C) in the CNS are presynaptic autoreceptors and serve to reduce NE release. Beta receptors (beta-1, beta-2, beta-3) inhibit cyclic adenosine monophosphate (cAMP) production.⁵⁹ The effects of inhibition of alpha or beta receptors are different. Inhibition of beta receptors is associated with depressive symptoms and depressive syndrome, inhibition of peripheral beta receptors is associated with reductions in anxiety (generally reduction of pulse, sweating, tremor),⁶⁰ and inhibition of central alpha-1 receptors is associated with reduced PTSD symptoms.⁶¹

Choice of agents for PTSD-specific symptoms

As outlined in the Table,⁸ PTSD is characterized by 3 types of symptoms that are specific for PTSD. Trauma-focused psychotherapy^62,63 and selective serotonin reuptake inhibitors (SSRIs)⁶⁴ are considered first-line therapy for PTSD. Only sertraline and paroxetine are FDA-approved for treating PTSD. However, the effect size for SSRIs is quite small; improvement is only 23% to 30% greater than placebo.^64,65 Furthermore, studies have shown that these medications have little effect on insomnia, hyperarousal, or other PTSD-specific symptoms.^66,67 Studies examining military veterans with PTSD have found that these patients tend to have little or no response to antidepressants.^68,69

Continue to: Serotonin transporter promoter...

Serotonin transporter promoter region gene short-type variants, which possibly increase an individual’s predisposition to developing PTSD, may explain the abundance of depressive symptoms in this condition and the subdued response to antidepressants. Specifically, an anticipated preponderance of these alleles may be associated with poorer outcomes. Non-SSRI treatments, such as low-dose aripiprazole, may be alternatives,⁷⁰ but these approaches have not been adequately developed.

On the other hand, animal models support antagonism of the postsynaptic alpha-1 adrenergic receptor of the CNS as a target for PTSD treatment.⁷¹ Although prazosin is not currently FDA-approved for treating PTSD, in placebo-controlled studies, nightmares and PTSD total symptoms improved with prazosin, and evidence suggests that it should be used 2 or 3 times a day for all PTSD symptoms.⁶¹ Prazosin may be helpful for treating sleep problems commonly experienced by people with PTSD. Blockade of histamine will also improve sleep disturbance and reduce nightmares, but it may not be as effective as prazosin.⁷²

Quetiapine might be another non-SSRI option for treating patients with PTSD. It is an antagonist with high affinity tothehistamine-1 receptor at low doses. Norquetiapine is an alpha-2 antagonist that increases brain NE levels. Both quetiapine and norquetiapine are alpha-1 antagonists. There is no beta blockade and no SSRI effect, but some 5HT2A blockade, which may be anxiolytic. Compared with placebo, an average quetiapine dose of 258 mg/d resulted in significantly greater reductions in Clinician-Administered PTSD Scale total score, re-experiencing score, and hyperarousal score.⁷³

Unfortunately, none of the non-SSRI options have been adequately evaluated. For now, clinicians need to continue to use SSRIs, and researchers need to continue to explore mechanism-guided alternatives.

Bottom Line

Understanding the mechanisms of the pathophysiology of posttraumatic stress disorder (PTSD) may allow clinicians to “jump ahead” of clinical studies and FDA indications. Clinicians may reasonably use alpha-1 antagonists (eg, prazosin, quetiapine) for general clinical improvement of patients with PTSD, particularly for PTSD-specific symptoms. Using antihistamines to reduce anxiety (especially in patients who have the COMT Val158Met polymorphism) may also be reasonable.

Related Resources

• North CS, Hong BA, Downs DL. PTSD: a systematic approach to diagnosis and treatment. Current Psychiatry. 2018;17(4):35-43.
• Zhang Y, Ren R, Sanford LD, et al. The effects of prazosin on sleep disturbances in post-traumatic stress disorder: a systematic review and meta-analysis. Sleep Med. 2019; 67:225-231.

Drug Brand Names

Aripiprazole • Abilify
Citalopram • Celexa
Paroxetine • Paxil
Prazosin • Minipress
Quetiapine • Seroquel
Sertraline • Zoloft

Posttraumatic stress disorder (PTSD) occurs acutely and chronically in the aftermath of severe and potentially life-threatening trauma.¹ The prevalence of PTSD varies significantly across countries and by type of trauma (Box^1-7).

Box

Individuals who develop PTSD experience a wide range of symptoms.⁸ These can be categorized as PTSD-specific symptoms, or nonspecific symptoms. PTSD-specific symptoms include nightmares, flashbacks, dissociative reactions, hyperreactivity or hyperarousal, distress with reminders of trauma, and avoidance of trauma-related physical reminders and thoughts/feelings (Table⁸). Nonspecific symptoms include depressive and anxiety symptoms and significant problems in social, relationship, or work situations.⁸

While successful treatment necessitates taking all of these symptoms into account, understanding the pathophysiology of PTSD can inform a more focused and ration­al treatment approach. In this article, we describe some key pathophysiologic PTSD studies, and focus on PTSD-specific psychopathology to inform treatment.

Brain systems implicated in PTSD

Neuropeptide Y (NPY) is an anxiolytic endogenous peptide that has connections to the hypothalamic-pituitary-adrenal (HPA) axis. Its levels can be modulated by stress.⁹ Preclinical and clinical studies strongly support a potential role of NPY dysfunction in the pathophysiology of PTSD. Lower concentrations of NPY increase susceptibility to PTSD in combat veterans¹⁰ and in animal models.¹¹ Three single-nucleotide polymorphisms (SNPs) appear to mediate this effect.¹² These findings strongly support pharmaceutical targeting this system as a useful therapeutic approach.^13,14 Indeed, intranasal NPY administered as a single dose reduces anxiety in animal models¹⁵ and in humans,¹⁶ but this work has not yet translated into clinical tools.

Corticotropin-releasing hormone receptor (CRHR1) gene. Corticotropin-releasing hormone has been implicated in PTSD.¹⁷ Corticotropin-releasing hormone receptors (CRHR) are important mediators in response to stress.^18,19 They bind corticotropin-releasing hormone and contribute to the integration of autonomic, behavioral, and immune responses to stress.²⁰ Single-nucleotide polymorphisms in the regulatory portion of the CRHR1 gene are associated with an increased risk for depression in adults who have a history of child abuse.²¹

The CRHR1 receptor antagonist GSK561679 is an investigational agent for the treatment of mood and anxiety disorders.²² In exploratory studies,^23,24 GSK561679 was found to inhibit fear-potentiated startle in patients with PTSD, but not overall PTSD symptoms, although a subset of women with a specific genetic variant of the CRHR1 gene (rs110402) experienced significant benefit.^25,26 This suggests that we must learn more about this system before we proceed.²⁷

Brain-derived neurotrophic factor (BDNF). The synthesis of BDNF is influenced by neuronal activity in the brain and plays a role in synaptic transmission and plasticity.²⁸ Brain-derived neuro­trophic factor is encoded by the BDNF gene, which has been implicated in stress vulnerability.²⁹ A common SNP in the pro-region of the human BDNF gene results in a valine-to-methionine substitution at the 66th amino acid (Val66Met). The functional Val66Met polymorphism may have a role in the risk of developing PTSD. However, not all studies support this finding. One study found that an SNP with a resulting Val66Met polymorphism is associated with adult PTSD symptoms after childhood abuse, while a meta-analysis of 7 studies did not confirm this.^30,31 We need to learn more about BDNF before we proceed.³²

Continue to: Serotonin transporter (5-HTT) gene

Serotonin transporter (5-HTT) gene. Serotonin transporter is a monoamine transporter protein that terminates the neurotransmitter signal by transporting serotonin from the synaptic cleft back into the presynaptic neuron. It is encoded by the SLC6A4 gene, which resides on the long arm of chromosome 17(17q11.1-q12). It is a large gene with 31 kilo bases and 14 separate exons (transcribed regions).^33,34

This gene has several variants. The best-studied is a variation in the promoter region. A 44-bp insertion or deletion yields the “long” and “short” alleles, respectively. The proteins produced by the 2 alleles are identical, but the amount of expressed protein is different. The short allele (“S”) is associated with a nearly 50% reduction in 5-HTT expression in both homozygotes and heterozygotes.³⁵ A greater incidence of serotonin transporter promoter region (5-HTTLPR) S has been found in individuals with PTSD compared with those without PTSD,^36-38 and 5-HTTLPR S increases the risk of PTSD in individuals with low social support³⁹ or after very few traumatic events.⁴⁰ The short allele variant is also associated with depression in individuals who face adversity.^35,41

The overrepresentation of the short form of 5-HTTLPR in individuals who develop PTSD may represent a potential problem with current treatment paradigms, in which an antidepressant is the first-line treatment, because this allele is associated with reduced response to antidepressants.^42,43 More distressing is the possible association of this allele with increased suicide risk, particularly violent suicide⁴⁴ or repeated suicide attempts.⁴⁵

Furthermore, a functional MRI study of patients who were anxious revealed that in individuals with the short allele, administration of citalopram was associated with increased amygdala activity in response to negative stimuli, and reduced activity in response to positive stimuli.⁴⁶ This suggests that antidepressant treatment may actually worsen fear response in patients with PTSD. Clearly, additional research is needed to determine if having the SLC6A4 gene alters clinical outcomes in response to an antidepressant in a patient with PTSD. In the meantime, clinicians should use vigilance and a critical mindset when they administer antidepressants to a patient who has PTSD.

Catechol-o-methyltransferase (COMT) is one of the enzymes that degrades catecholamines such as dopamine, epinephrine, and norepinephrine (NE).⁴⁷ In humans, COMT protein is encoded by the COMT gene. This gene is associated with allelic variants; the best-studied of these is Val158Met. COMT Val158Met polymorphism (rs4860) has been linked to deficits in stress response and emotional resilience.^48,49 Val158Met is associated with a 40% reduction in enzyme activity and slower catalysis of catecholamines, resulting in increases in catecholamines levels in the brain, which may increase the risk of developing PTSD.⁵⁰ Individuals homozygous for this SNP (Met/Met) are highly susceptible to develop PTSD independently of the severity of the trauma they experienced.⁵¹ The Val158Met polymorphism may be associated with other abnormalities, such as cognitive problems with specific frontal cortical activity, and also with improved antidepressant response (valine homozygotes less responsive than methionine homozygotes).⁵² This gene is available on gene testing profiles.

Continue to: The role of norepinephrine in PTSD

The role of norepinephrine in PTSD

Perhaps the greatest advance in the understanding of the pathophysiology of PTSD relates to changes in brain NE. The HPA axis is responsible for coordinating the hormonal response to stress. Dysregulation of this axis and increased activity of the central and peripheral noradrenergic systems are usually observed in patients with PTSD.⁵³ Several monoamine neurotransmitters are important in the regulation and function of the HPA axis. Norepinephrine plays a major role in stress.

The clinical PTSD-specific criteria are all descriptions of excessive noradrenergic tone.⁵⁴ For example, hypervigilance and hyperstartle are clearly anticipated as evidence of NE stimulation. Flashbacks, particularly those that might be precipitated by environmental cues, also can be a manifestation of the vigilance induced by NE. Sleep disturbances (insomnia and nightmares) are present; insomnia is reported more often than nightmares.⁵⁵ Increased catecholamine levels, particularly NE, are a feature of sleep disturbances associated with middle insomnia. Dreams can be remembered only if you wake up during dreaming. Catecholamines do not change the content of dreams, just recall.⁵⁶

In a study of central noradrenergic tone in patients with PTSD, 6 hourly CSF samples were collected from 11 male combat veterans with PTSD and 8 healthy controls.⁵⁷ Participants with PTSD had significantly higher CSF NE concentrations (0.55 ± 0.17 pmol/ml vs 0.39 ± 0.16 pmol/mL in the PTSD and control groups, respectively; F = 4.49, P < .05).⁵⁷ Overall PTSD symptoms correlated significantly with CSF NE levels (r = 0.82, P <.005), and PTSD-specific symptoms such as avoidance (r = 0.79, P = .004). Intrusive thoughts (r = 0.57, P = .07) and hyperarousal (r = 0.54, P = .09) were also related.⁵⁷ This relationship is unique; patients with PTSD with predominant depressive symptoms do not have elevated plasma NE levels.⁵⁸

In the human brain, there are 3 main groups of NE receptors: alpha-1 receptors, alpha-2 receptors, and beta receptors.⁵⁹ Alpha-1 receptors (alpha-1A, alpha-1B, and alpha-1D) are postsynaptic and mediate increase in inositol trisphosphate (IP₃) and intracellular calcium (Ca²⁺). Alpha-2 receptors (alpha-2A, alpha-2B, alpha-2C) in the CNS are presynaptic autoreceptors and serve to reduce NE release. Beta receptors (beta-1, beta-2, beta-3) inhibit cyclic adenosine monophosphate (cAMP) production.⁵⁹ The effects of inhibition of alpha or beta receptors are different. Inhibition of beta receptors is associated with depressive symptoms and depressive syndrome, inhibition of peripheral beta receptors is associated with reductions in anxiety (generally reduction of pulse, sweating, tremor),⁶⁰ and inhibition of central alpha-1 receptors is associated with reduced PTSD symptoms.⁶¹

Choice of agents for PTSD-specific symptoms

As outlined in the Table,⁸ PTSD is characterized by 3 types of symptoms that are specific for PTSD. Trauma-focused psychotherapy^62,63 and selective serotonin reuptake inhibitors (SSRIs)⁶⁴ are considered first-line therapy for PTSD. Only sertraline and paroxetine are FDA-approved for treating PTSD. However, the effect size for SSRIs is quite small; improvement is only 23% to 30% greater than placebo.^64,65 Furthermore, studies have shown that these medications have little effect on insomnia, hyperarousal, or other PTSD-specific symptoms.^66,67 Studies examining military veterans with PTSD have found that these patients tend to have little or no response to antidepressants.^68,69

Continue to: Serotonin transporter promoter...

Serotonin transporter promoter region gene short-type variants, which possibly increase an individual’s predisposition to developing PTSD, may explain the abundance of depressive symptoms in this condition and the subdued response to antidepressants. Specifically, an anticipated preponderance of these alleles may be associated with poorer outcomes. Non-SSRI treatments, such as low-dose aripiprazole, may be alternatives,⁷⁰ but these approaches have not been adequately developed.

On the other hand, animal models support antagonism of the postsynaptic alpha-1 adrenergic receptor of the CNS as a target for PTSD treatment.⁷¹ Although prazosin is not currently FDA-approved for treating PTSD, in placebo-controlled studies, nightmares and PTSD total symptoms improved with prazosin, and evidence suggests that it should be used 2 or 3 times a day for all PTSD symptoms.⁶¹ Prazosin may be helpful for treating sleep problems commonly experienced by people with PTSD. Blockade of histamine will also improve sleep disturbance and reduce nightmares, but it may not be as effective as prazosin.⁷²

Quetiapine might be another non-SSRI option for treating patients with PTSD. It is an antagonist with high affinity tothehistamine-1 receptor at low doses. Norquetiapine is an alpha-2 antagonist that increases brain NE levels. Both quetiapine and norquetiapine are alpha-1 antagonists. There is no beta blockade and no SSRI effect, but some 5HT2A blockade, which may be anxiolytic. Compared with placebo, an average quetiapine dose of 258 mg/d resulted in significantly greater reductions in Clinician-Administered PTSD Scale total score, re-experiencing score, and hyperarousal score.⁷³

Unfortunately, none of the non-SSRI options have been adequately evaluated. For now, clinicians need to continue to use SSRIs, and researchers need to continue to explore mechanism-guided alternatives.

Bottom Line

Understanding the mechanisms of the pathophysiology of posttraumatic stress disorder (PTSD) may allow clinicians to “jump ahead” of clinical studies and FDA indications. Clinicians may reasonably use alpha-1 antagonists (eg, prazosin, quetiapine) for general clinical improvement of patients with PTSD, particularly for PTSD-specific symptoms. Using antihistamines to reduce anxiety (especially in patients who have the COMT Val158Met polymorphism) may also be reasonable.

Related Resources

• North CS, Hong BA, Downs DL. PTSD: a systematic approach to diagnosis and treatment. Current Psychiatry. 2018;17(4):35-43.
• Zhang Y, Ren R, Sanford LD, et al. The effects of prazosin on sleep disturbances in post-traumatic stress disorder: a systematic review and meta-analysis. Sleep Med. 2019; 67:225-231.

Drug Brand Names

Aripiprazole • Abilify
Citalopram • Celexa
Paroxetine • Paxil
Prazosin • Minipress
Quetiapine • Seroquel
Sertraline • Zoloft

Most clinicians do not think about receptor occupancy when they prescribe a medication. Most simply assume that if they use a low dose of a medication, they will get a small effect, and if they use a higher dose, they will get a larger effect. However, this is frequently not accurate. Clinicians need to understand the relationship between receptor occupancy and drug response.

In general, when an antagonist of a neurotransmitter receptor is used, it must occupy a minimum of 65% to 70% of the target receptor to be effective. This is clearly the case when the target is a postsynaptic receptor, such as the dopamine D2 receptor.^1-3 Similarly, despite significant variability in antidepressant response,⁴ blockade of 65% to 80% of presynaptic transport proteins—such as the serotonin reuptake pumps when considering serotoninergic antidepressants,^5,6 or the norepinephrine reuptake pumps when considering noradrenergic agents such as nortriptyline⁷—is necessary for these medications to be effective.

It is reasonable to think of the drug response of such agents as following a “threshold” model (Figure 1). This model makes 2 predictions. The first prediction is that a low dose of the drug might result in <50% receptor occupancy, but is not associated with a smaller response; it is simply ineffective. The second prediction is that a very high dose of the drug (eg, one that may exceed 90% receptor occupancy) does not result in any additional benefit, but may cause additional adverse consequences.⁸

Alternatively, agonist medications, such as benzodiazepines or opiates, have their efficacy in a continuous dose-dependent fashion (Figure 2). Titrating these medications for clinical response is necessary, and minimal effective doses are highly individual. Agonist medications will not be addressed further in this article.

In this article, the term “response” is used to denote the average (population) symptom change in a study population. This term is not used as clinicians often use it to mean that their specific patient’s illness has improved, or that the patient has gone into remission. Furthermore, the information described in this article does not optimize clinical outcome, but instead is intended to help clinicians optimize the use of their pharmacologic tools.

Minimal effective dose

Medications that have a threshold for activity will display that clinically in a minimal effective dose (Table 1^3,9 and Table 2⁵). The minimal effective dose of medications that act by blocking a neurotransmitter receptor is usually the dose that achieves 65% to 80% receptor occupancy in typical individuals (Table 2⁵). The minimal effective doses for antipsychotics are listed in Table 1.^3,9 These doses are known to occupy approximately 65% to 70% of postsynaptic D2 receptors in living humans as confirmed by positron emission tomography (PET) scans.¹⁰ Similar minimal effective doses can be determined for serotonin-reuptake inhibiting (SRI) antidepressants (Table 2⁵). In placebo-controlled trials, doses that were smaller than the minimal effective dose did not provide any benefit.

There are important caveats to this. First is the use of partial agonists. Depending on the level of intrinsic activity of a partial agonist and clinical goal, the clinician may aim for a different level of receptor occupancy. For example, aripiprazole will act as a dopamine agonist at lower concentrations, but blocks the receptor at higher concentrations.¹¹ Unlike antagonist antipsychotics, which require only 65% to 70% D2 receptor occupancy to be effective, aripiprazole receptor binding at effective antipsychotic doses is 90% to 95%.^12-14 Since aripiprazole has an intrinsic activity of approximately 30% (ie, when it binds, it stimulates the D2 receptor to about 30% of the effect of dopamine binding to the receptor¹⁵), binding to 90% of the receptors, and displacing endogenous dopamine, allows aripiprazole to replace the background or tonic tone of dopamine, which has been measured at 19% in people with schizophrenia and 9% in controls.¹⁶ Clinically, this still appears as the minimal effective dose achieving maximal response^17-19 without significant parkinsonism despite >90% receptor occupancy.¹²

Continue to: The second caveat is...

The second caveat is the action of low D2 receptor affinity antipsychotics, such as clozapine and quetiapine. These agents generally achieve adequate D2 receptor occupancy for only a brief period of time.²⁰ It has been suggested that continuous receptor occupancy at ≥65% may not be necessary to obtain antipsychotic control.^21,22 There may also be specific limbic and cortical (vs striatal) D2 receptor selectivity by cloza­pine²³ compared with other second-generation antipsychotics such as risperidone and olanzapine,^24,25 although this point remains debatable.²⁶ Furthermore, the antipsychotic efficacy of low D2 receptor affinity drugs is unreliable, even in controlled, blinded studies (eg, a failed large quetiapine study²⁷). Thus far, the actual antipsychotic mechanism of these agents is yet to be fully understood.

Minimal effective dose achieves maximal response

An interesting aspect of the threshold phenomenon of drug response is that once the minimal effective dose is reached, maximal response is achieved. In other words, there is no additional efficacy with additional dose increases. This is readily demonstrated in some studies in which patients were randomly assigned to different fixed doses or dose ranges. In these studies, there was generally no difference in response rates of different doses, so that once 65% to 80% receptor occupancy is achieved, minimal and maximal clinical response is simultaneously reached.^18,28,29

For example, in the original risperidone studies, 6 mg/d was essentially equivalent to 16 mg/d.²⁸ Similarly, lurasidone, 40 mg/d, achieves approximately 65% D2 occupancy.³⁰ When the daily dose is increased to 120 mg, there is no additional benefit in controlling psychosis in schizophrenia.²⁹ This pattern is also seen in partial agonists, where there are no differences between lower and higher doses in terms of response.¹⁸

Upon reading this, many clinicians may think “I don’t care what the studies say, I have seen additional benefits with additional doses.” There are several explanations for this. One is that individual patients have genetic variants that may prevent them from responding in a typical fashion. Hints of this are seen in an apparent disconnect between dosage and drug levels, so that it is not surprising that drug levels are a much better predictor of receptor occupancy than dosage.³¹ Nonetheless, as previously pointed out, for a population, dosage does predict receptor occupancy and outcome. However, for individuals, genetic variations make dosages less reliable. For example, ultrarapid metabolizers of cytochrome P450 (CYP) 2D6 may discontinue risperidone due to nonresponse, or require a higher dose or longer time period to respond.^32,33 Similarly, patients who smoke may require an increase in doses of CYP1A2 substrates such as clozapine and olanzapine.³⁴

Alternatively, the clinician may note improvement in mood, sleep, appetite, or other symptoms at lower doses, and then note additional improvements in psychosis or mania at higher doses.³ This occurs due to the varying affinity of different receptors. For example, in bipolar depression trials that used quetiapine in a fixed-dose design, patients who received 300 or 600 mg/d responded in the same fashion, with no additional benefit in improving depression with the higher dose.³⁵ Similarly, in a flexible dose range study that evaluated lurasidone in bipolar depression, an average dose of 34 mg/d (range 20 to 60 mg/d) and an average dose of 83 mg/d (range 80 to 120 mg/d) both resulted in the same response (a 15.4-point reduction in depression ratings and an effect size of 0.51).³⁶ For both quetiapine and lurasidone, higher doses are generally required to control psychosis.^29,37 Note that for lurasidone, agitation, but not psychosis, improves with higher doses, which suggests that recruitment of additional receptors results in improvement in a different set of symptoms.⁹

Continue to: Clinical implications

The implications for clinicians are relatively clear. Knowing the minimal effective doses for depression, psychosis, or mania informs the target dose. If improvement is seen at lower doses, the clinician needs to assess the profile of symptoms that improved, potential drug–drug interactions, or potential irregularities in the patient’s metabolic pathways. Clinicians need to increase doses above the minimally effective dose carefully, and expend additional effort in analyzing changes in their patient’s symptoms and adverse effects; this analysis should be performed with skepticism and willingness to reduce a dosage if no additional benefit is seen. Attention to these receptor-symptom interactions will improve response and reduce adverse consequences in the majority of patients.

Related Resource

• Lako IM, van den Heuvel ER, Knegtering H, et al. Estimating dopamine D2 receptor occupancy for doses of 8 antipsychotics: a meta-analysis. J Clin Psychopharmacol. 2013;33(5):675-681.

Drug Brand Names

Aripiprazole • Abilify
Asenapine • Saphris
Citalopram • Celexa
Clozapine • Clozaril
Fluoxetine • Prozac
Haloperidol • Haldol
Iloperidone • Fanapt
Lurasidone • Latuda
Nortriptyline • Pamelor
Olanzapine • Zyprexa
Paroxetine • Paxil
Quetiapine • Seroquel
Risperidone • Risperdal
Sertraline • Zoloft
Venlafaxine • Effexor
Ziprasidone • Geodon

Most clinicians do not think about receptor occupancy when they prescribe a medication. Most simply assume that if they use a low dose of a medication, they will get a small effect, and if they use a higher dose, they will get a larger effect. However, this is frequently not accurate. Clinicians need to understand the relationship between receptor occupancy and drug response.

In general, when an antagonist of a neurotransmitter receptor is used, it must occupy a minimum of 65% to 70% of the target receptor to be effective. This is clearly the case when the target is a postsynaptic receptor, such as the dopamine D2 receptor.^1-3 Similarly, despite significant variability in antidepressant response,⁴ blockade of 65% to 80% of presynaptic transport proteins—such as the serotonin reuptake pumps when considering serotoninergic antidepressants,^5,6 or the norepinephrine reuptake pumps when considering noradrenergic agents such as nortriptyline⁷—is necessary for these medications to be effective.

It is reasonable to think of the drug response of such agents as following a “threshold” model (Figure 1). This model makes 2 predictions. The first prediction is that a low dose of the drug might result in <50% receptor occupancy, but is not associated with a smaller response; it is simply ineffective. The second prediction is that a very high dose of the drug (eg, one that may exceed 90% receptor occupancy) does not result in any additional benefit, but may cause additional adverse consequences.⁸

Alternatively, agonist medications, such as benzodiazepines or opiates, have their efficacy in a continuous dose-dependent fashion (Figure 2). Titrating these medications for clinical response is necessary, and minimal effective doses are highly individual. Agonist medications will not be addressed further in this article.

In this article, the term “response” is used to denote the average (population) symptom change in a study population. This term is not used as clinicians often use it to mean that their specific patient’s illness has improved, or that the patient has gone into remission. Furthermore, the information described in this article does not optimize clinical outcome, but instead is intended to help clinicians optimize the use of their pharmacologic tools.

Minimal effective dose

Medications that have a threshold for activity will display that clinically in a minimal effective dose (Table 1^3,9 and Table 2⁵). The minimal effective dose of medications that act by blocking a neurotransmitter receptor is usually the dose that achieves 65% to 80% receptor occupancy in typical individuals (Table 2⁵). The minimal effective doses for antipsychotics are listed in Table 1.^3,9 These doses are known to occupy approximately 65% to 70% of postsynaptic D2 receptors in living humans as confirmed by positron emission tomography (PET) scans.¹⁰ Similar minimal effective doses can be determined for serotonin-reuptake inhibiting (SRI) antidepressants (Table 2⁵). In placebo-controlled trials, doses that were smaller than the minimal effective dose did not provide any benefit.

There are important caveats to this. First is the use of partial agonists. Depending on the level of intrinsic activity of a partial agonist and clinical goal, the clinician may aim for a different level of receptor occupancy. For example, aripiprazole will act as a dopamine agonist at lower concentrations, but blocks the receptor at higher concentrations.¹¹ Unlike antagonist antipsychotics, which require only 65% to 70% D2 receptor occupancy to be effective, aripiprazole receptor binding at effective antipsychotic doses is 90% to 95%.^12-14 Since aripiprazole has an intrinsic activity of approximately 30% (ie, when it binds, it stimulates the D2 receptor to about 30% of the effect of dopamine binding to the receptor¹⁵), binding to 90% of the receptors, and displacing endogenous dopamine, allows aripiprazole to replace the background or tonic tone of dopamine, which has been measured at 19% in people with schizophrenia and 9% in controls.¹⁶ Clinically, this still appears as the minimal effective dose achieving maximal response^17-19 without significant parkinsonism despite >90% receptor occupancy.¹²

Continue to: The second caveat is...

The second caveat is the action of low D2 receptor affinity antipsychotics, such as clozapine and quetiapine. These agents generally achieve adequate D2 receptor occupancy for only a brief period of time.²⁰ It has been suggested that continuous receptor occupancy at ≥65% may not be necessary to obtain antipsychotic control.^21,22 There may also be specific limbic and cortical (vs striatal) D2 receptor selectivity by cloza­pine²³ compared with other second-generation antipsychotics such as risperidone and olanzapine,^24,25 although this point remains debatable.²⁶ Furthermore, the antipsychotic efficacy of low D2 receptor affinity drugs is unreliable, even in controlled, blinded studies (eg, a failed large quetiapine study²⁷). Thus far, the actual antipsychotic mechanism of these agents is yet to be fully understood.

Minimal effective dose achieves maximal response

An interesting aspect of the threshold phenomenon of drug response is that once the minimal effective dose is reached, maximal response is achieved. In other words, there is no additional efficacy with additional dose increases. This is readily demonstrated in some studies in which patients were randomly assigned to different fixed doses or dose ranges. In these studies, there was generally no difference in response rates of different doses, so that once 65% to 80% receptor occupancy is achieved, minimal and maximal clinical response is simultaneously reached.^18,28,29

For example, in the original risperidone studies, 6 mg/d was essentially equivalent to 16 mg/d.²⁸ Similarly, lurasidone, 40 mg/d, achieves approximately 65% D2 occupancy.³⁰ When the daily dose is increased to 120 mg, there is no additional benefit in controlling psychosis in schizophrenia.²⁹ This pattern is also seen in partial agonists, where there are no differences between lower and higher doses in terms of response.¹⁸

Upon reading this, many clinicians may think “I don’t care what the studies say, I have seen additional benefits with additional doses.” There are several explanations for this. One is that individual patients have genetic variants that may prevent them from responding in a typical fashion. Hints of this are seen in an apparent disconnect between dosage and drug levels, so that it is not surprising that drug levels are a much better predictor of receptor occupancy than dosage.³¹ Nonetheless, as previously pointed out, for a population, dosage does predict receptor occupancy and outcome. However, for individuals, genetic variations make dosages less reliable. For example, ultrarapid metabolizers of cytochrome P450 (CYP) 2D6 may discontinue risperidone due to nonresponse, or require a higher dose or longer time period to respond.^32,33 Similarly, patients who smoke may require an increase in doses of CYP1A2 substrates such as clozapine and olanzapine.³⁴

Alternatively, the clinician may note improvement in mood, sleep, appetite, or other symptoms at lower doses, and then note additional improvements in psychosis or mania at higher doses.³ This occurs due to the varying affinity of different receptors. For example, in bipolar depression trials that used quetiapine in a fixed-dose design, patients who received 300 or 600 mg/d responded in the same fashion, with no additional benefit in improving depression with the higher dose.³⁵ Similarly, in a flexible dose range study that evaluated lurasidone in bipolar depression, an average dose of 34 mg/d (range 20 to 60 mg/d) and an average dose of 83 mg/d (range 80 to 120 mg/d) both resulted in the same response (a 15.4-point reduction in depression ratings and an effect size of 0.51).³⁶ For both quetiapine and lurasidone, higher doses are generally required to control psychosis.^29,37 Note that for lurasidone, agitation, but not psychosis, improves with higher doses, which suggests that recruitment of additional receptors results in improvement in a different set of symptoms.⁹

Continue to: Clinical implications

The implications for clinicians are relatively clear. Knowing the minimal effective doses for depression, psychosis, or mania informs the target dose. If improvement is seen at lower doses, the clinician needs to assess the profile of symptoms that improved, potential drug–drug interactions, or potential irregularities in the patient’s metabolic pathways. Clinicians need to increase doses above the minimally effective dose carefully, and expend additional effort in analyzing changes in their patient’s symptoms and adverse effects; this analysis should be performed with skepticism and willingness to reduce a dosage if no additional benefit is seen. Attention to these receptor-symptom interactions will improve response and reduce adverse consequences in the majority of patients.

Related Resource

• Lako IM, van den Heuvel ER, Knegtering H, et al. Estimating dopamine D2 receptor occupancy for doses of 8 antipsychotics: a meta-analysis. J Clin Psychopharmacol. 2013;33(5):675-681.

Drug Brand Names

Aripiprazole • Abilify
Asenapine • Saphris
Citalopram • Celexa
Clozapine • Clozaril
Fluoxetine • Prozac
Haloperidol • Haldol
Iloperidone • Fanapt
Lurasidone • Latuda
Nortriptyline • Pamelor
Olanzapine • Zyprexa
Paroxetine • Paxil
Quetiapine • Seroquel
Risperidone • Risperdal
Sertraline • Zoloft
Venlafaxine • Effexor
Ziprasidone • Geodon

Most clinicians do not think about receptor occupancy when they prescribe a medication. Most simply assume that if they use a low dose of a medication, they will get a small effect, and if they use a higher dose, they will get a larger effect. However, this is frequently not accurate. Clinicians need to understand the relationship between receptor occupancy and drug response.

In general, when an antagonist of a neurotransmitter receptor is used, it must occupy a minimum of 65% to 70% of the target receptor to be effective. This is clearly the case when the target is a postsynaptic receptor, such as the dopamine D2 receptor.^1-3 Similarly, despite significant variability in antidepressant response,⁴ blockade of 65% to 80% of presynaptic transport proteins—such as the serotonin reuptake pumps when considering serotoninergic antidepressants,^5,6 or the norepinephrine reuptake pumps when considering noradrenergic agents such as nortriptyline⁷—is necessary for these medications to be effective.

It is reasonable to think of the drug response of such agents as following a “threshold” model (Figure 1). This model makes 2 predictions. The first prediction is that a low dose of the drug might result in <50% receptor occupancy, but is not associated with a smaller response; it is simply ineffective. The second prediction is that a very high dose of the drug (eg, one that may exceed 90% receptor occupancy) does not result in any additional benefit, but may cause additional adverse consequences.⁸

Alternatively, agonist medications, such as benzodiazepines or opiates, have their efficacy in a continuous dose-dependent fashion (Figure 2). Titrating these medications for clinical response is necessary, and minimal effective doses are highly individual. Agonist medications will not be addressed further in this article.

In this article, the term “response” is used to denote the average (population) symptom change in a study population. This term is not used as clinicians often use it to mean that their specific patient’s illness has improved, or that the patient has gone into remission. Furthermore, the information described in this article does not optimize clinical outcome, but instead is intended to help clinicians optimize the use of their pharmacologic tools.

Minimal effective dose

Medications that have a threshold for activity will display that clinically in a minimal effective dose (Table 1^3,9 and Table 2⁵). The minimal effective dose of medications that act by blocking a neurotransmitter receptor is usually the dose that achieves 65% to 80% receptor occupancy in typical individuals (Table 2⁵). The minimal effective doses for antipsychotics are listed in Table 1.^3,9 These doses are known to occupy approximately 65% to 70% of postsynaptic D2 receptors in living humans as confirmed by positron emission tomography (PET) scans.¹⁰ Similar minimal effective doses can be determined for serotonin-reuptake inhibiting (SRI) antidepressants (Table 2⁵). In placebo-controlled trials, doses that were smaller than the minimal effective dose did not provide any benefit.

There are important caveats to this. First is the use of partial agonists. Depending on the level of intrinsic activity of a partial agonist and clinical goal, the clinician may aim for a different level of receptor occupancy. For example, aripiprazole will act as a dopamine agonist at lower concentrations, but blocks the receptor at higher concentrations.¹¹ Unlike antagonist antipsychotics, which require only 65% to 70% D2 receptor occupancy to be effective, aripiprazole receptor binding at effective antipsychotic doses is 90% to 95%.^12-14 Since aripiprazole has an intrinsic activity of approximately 30% (ie, when it binds, it stimulates the D2 receptor to about 30% of the effect of dopamine binding to the receptor¹⁵), binding to 90% of the receptors, and displacing endogenous dopamine, allows aripiprazole to replace the background or tonic tone of dopamine, which has been measured at 19% in people with schizophrenia and 9% in controls.¹⁶ Clinically, this still appears as the minimal effective dose achieving maximal response^17-19 without significant parkinsonism despite >90% receptor occupancy.¹²

Continue to: The second caveat is...

The second caveat is the action of low D2 receptor affinity antipsychotics, such as clozapine and quetiapine. These agents generally achieve adequate D2 receptor occupancy for only a brief period of time.²⁰ It has been suggested that continuous receptor occupancy at ≥65% may not be necessary to obtain antipsychotic control.^21,22 There may also be specific limbic and cortical (vs striatal) D2 receptor selectivity by cloza­pine²³ compared with other second-generation antipsychotics such as risperidone and olanzapine,^24,25 although this point remains debatable.²⁶ Furthermore, the antipsychotic efficacy of low D2 receptor affinity drugs is unreliable, even in controlled, blinded studies (eg, a failed large quetiapine study²⁷). Thus far, the actual antipsychotic mechanism of these agents is yet to be fully understood.

Minimal effective dose achieves maximal response

An interesting aspect of the threshold phenomenon of drug response is that once the minimal effective dose is reached, maximal response is achieved. In other words, there is no additional efficacy with additional dose increases. This is readily demonstrated in some studies in which patients were randomly assigned to different fixed doses or dose ranges. In these studies, there was generally no difference in response rates of different doses, so that once 65% to 80% receptor occupancy is achieved, minimal and maximal clinical response is simultaneously reached.^18,28,29

For example, in the original risperidone studies, 6 mg/d was essentially equivalent to 16 mg/d.²⁸ Similarly, lurasidone, 40 mg/d, achieves approximately 65% D2 occupancy.³⁰ When the daily dose is increased to 120 mg, there is no additional benefit in controlling psychosis in schizophrenia.²⁹ This pattern is also seen in partial agonists, where there are no differences between lower and higher doses in terms of response.¹⁸

Upon reading this, many clinicians may think “I don’t care what the studies say, I have seen additional benefits with additional doses.” There are several explanations for this. One is that individual patients have genetic variants that may prevent them from responding in a typical fashion. Hints of this are seen in an apparent disconnect between dosage and drug levels, so that it is not surprising that drug levels are a much better predictor of receptor occupancy than dosage.³¹ Nonetheless, as previously pointed out, for a population, dosage does predict receptor occupancy and outcome. However, for individuals, genetic variations make dosages less reliable. For example, ultrarapid metabolizers of cytochrome P450 (CYP) 2D6 may discontinue risperidone due to nonresponse, or require a higher dose or longer time period to respond.^32,33 Similarly, patients who smoke may require an increase in doses of CYP1A2 substrates such as clozapine and olanzapine.³⁴

Alternatively, the clinician may note improvement in mood, sleep, appetite, or other symptoms at lower doses, and then note additional improvements in psychosis or mania at higher doses.³ This occurs due to the varying affinity of different receptors. For example, in bipolar depression trials that used quetiapine in a fixed-dose design, patients who received 300 or 600 mg/d responded in the same fashion, with no additional benefit in improving depression with the higher dose.³⁵ Similarly, in a flexible dose range study that evaluated lurasidone in bipolar depression, an average dose of 34 mg/d (range 20 to 60 mg/d) and an average dose of 83 mg/d (range 80 to 120 mg/d) both resulted in the same response (a 15.4-point reduction in depression ratings and an effect size of 0.51).³⁶ For both quetiapine and lurasidone, higher doses are generally required to control psychosis.^29,37 Note that for lurasidone, agitation, but not psychosis, improves with higher doses, which suggests that recruitment of additional receptors results in improvement in a different set of symptoms.⁹

Continue to: Clinical implications

The implications for clinicians are relatively clear. Knowing the minimal effective doses for depression, psychosis, or mania informs the target dose. If improvement is seen at lower doses, the clinician needs to assess the profile of symptoms that improved, potential drug–drug interactions, or potential irregularities in the patient’s metabolic pathways. Clinicians need to increase doses above the minimally effective dose carefully, and expend additional effort in analyzing changes in their patient’s symptoms and adverse effects; this analysis should be performed with skepticism and willingness to reduce a dosage if no additional benefit is seen. Attention to these receptor-symptom interactions will improve response and reduce adverse consequences in the majority of patients.

Related Resource

• Lako IM, van den Heuvel ER, Knegtering H, et al. Estimating dopamine D2 receptor occupancy for doses of 8 antipsychotics: a meta-analysis. J Clin Psychopharmacol. 2013;33(5):675-681.

Drug Brand Names

Aripiprazole • Abilify
Asenapine • Saphris
Citalopram • Celexa
Clozapine • Clozaril
Fluoxetine • Prozac
Haloperidol • Haldol
Iloperidone • Fanapt
Lurasidone • Latuda
Nortriptyline • Pamelor
Olanzapine • Zyprexa
Paroxetine • Paxil
Quetiapine • Seroquel
Risperidone • Risperdal
Sertraline • Zoloft
Venlafaxine • Effexor
Ziprasidone • Geodon