Current Psychiatry

Lithium is among the most effective therapies for bipolar disorder (BD), and enthusiasm for this simple molecule is waxing. The his­tory of lithium is fascinating,¹ and recent considerations include that this element, the third on the periodic table, has few, if any, indus­try champions. The recent renaissance is caused by a groundswell of appreciation for the clinical efficacy of lithium and an increasing num­ber of providers who are willing to manage patients with lithium.

Target: Bipolar disorder
The target illness for lithium is BD, a spectrum of mood disorders with characteristic features of unstable mood and affect. Shifts in mood include recurrent episodes of mania, which are pathologically ener­gized states with misguided volition and behavior with intoxicating euphoria (or irritability).^₂ Psychomotor activity is elevated and out of character; speech and body movements are revved up, with a dimin­ished need for sleep. The social, personal, and vocational consequences often are disastrous.

The most common mood state of BD is depression. Depressive episodes consist of pathologically compromised energy and volition with a slowing of bodily functions, most prominently cognition and concentration; a pervasive depressed or sad mood is common but not always present. Presence of mixed states, when features of depression and mania are present simultaneously, is one of the many challenges of treating BD; an elevated volitional or energized state may occur with a depressed, dysphoric mood.

Evidence for lithium
Efficacy studies of lithium have focused on managing mood disorders, treating mania and depression, and prevention or main­tenance care.³ Most were performed dur­ing the 1970s and 1980s,³ but recent studies have been comparing lithium with other mood stabilizers^4-7 and searching for a genetic basis for lithium response.^8-10 Other researchers have examined the use of lith­ium to prevent suicide.¹¹ Some have sug­gested a neuroprotective effect of lithium, which may have profound implications for neuropsychiatry if valid.^12-14 Results of additional studies, which are at differ­ent stages of completion, will clarify lith­ium use,^15,16 and characterize the genetic makeup of individuals who respond to lithium.¹⁷ The primary evidence for lith­ium, however, is for maintenance treat­ment of BD and for preventing manic and depressive episodes.

Biochemistry and physiology of lithium. The biochemical and physiological effects of lithium are complex, wide-ranging, and likely to affect hundreds, if not thou­sands, of genes and gene products. The mechanisms of action remain a focus of aca­demic pursuit (for a review of hypotheses related to these mechanisms see Goodwin and Jamison² and Can et al¹⁸) Lithium is involved in cell signaling pathways that involve complex molecular mechanisms of inter- and intracellular communica­tion¹⁹; some neural receptors are down-regulated²⁰ and others show inhibition,²¹ which is thought to be a mechanism of lithium. The hypothesized neuroprotective effect of lithium²² may be mediated through an increased level of brain-derived neuro­trophic factor in brain tissue.¹⁴ Recently, investigators using induced pluripotent stem cell derived neurons have shown that patterns of calcium-related cell signaling in bipolar neurons are affected specifically by lithium in the culture media.²³ There likely are many mechanisms through which lithi­um’s effects are mediated, including a series of dynamic pathways that vary over time and in reaction to the internal and external environments of the cell and person.

The lithium renaissance
In the past decade, there has been an increase in interest and use of lithium because clinicians recognize its efficacy and advantages and can monitor serum levels and gauge the patient’s response and side effects²⁴ against the lithium level. This is important because balancing effi­ cacy and side effects depends on the serum level. Efficacy often is not immediate, although side effects may emerge early. All systems of the body may show effects that could be related to lithium use. It is helpful to be aware of the side effects in chronolog­ical order, because some immediate effects may be associated with starting at higher dosages (Table 1). Common side effects in the short term include:

   • GI distress, such as nausea, vomiting, diarrhea, and abdominal discomfort
   • a fine neurologic tremor, which may be seen with accentuation upon deliber­ate movement
   • prominent thirst with polyuria
   • drowsiness and clouded thinking, which can be upsetting to the patient and family.

In the longer term, adverse effects on kidney and thyroid function are common. Management must include monitoring of the serum level.

Lithium is FDA-approved for acute and maintenance treatment of mania in BD. There are reports that discuss most vari­ants of mood disorders, including BD I, BD II, unipolar depression, rapid cycling, and even alcohol abuse.^25-29 Lithium could help manage mood dysregulation in the context of temperament and personal­ity.³⁰ There is evidence that lithium has an antidepressant effect31-33 and has shown efficacy as an adjunctive treatment for depression.^31-33 There are data that sug­gest that lithium, with its neuroprotective mechanisms, may prevent progression of mild cognitive impairment.³⁴

Is there an ideal lithium candidate?
Mood instability is the characteristic fea­ture of a lithium responder. The instability may be over the course of the day, such as a dysregulated temperament that often is associated with DSM-IV personality cat­egories, shorter-term fluctuations (within days with BD II), or in the context of epi­sodic shifts of mood states over weeks and months, which are characteristic of BD I. The hallmark of mood instability is fluctuation from depression to elevated mood states and charged emotions with increased energy.

The patient considered ideal for lith­ium treatment has BD I with recurrent severe euphoric manic episodes, absence of significant comorbid disorders such as substance abuse, and a family history of lithium response. However, any patient with a clinically significant and unstable mood disorder, regardless of the DSM diagnosis, should be considered for lith­ium treatment.

When considering a lithium trial for a patient with significant mood instability, it is critical to establish the target symptoms and behavior that will help you gauge the efficacy of the intervention. Measurement-based care utilizes clinician and self-report instruments to provide data on the ill­ness course and response to interven­tion. Commonly used clinician driven assessments include the Young Mania Rating Scale³⁵ and the Quick Inventory of Depressive Symptoms,³⁶ while the self-report assessments are the Patient Health Questionnaire³⁷ and the Altman Self- Rating Mania Scale.³⁸

During acute mania or depression, lithium often is used in combination with another medications such as an antipsy­chotic or antidepressant. Used in the out­patient and non-acute setting, lithium may be an “add-on” or monotherapy for pre­venting recurrence of episodes. Response in early acute manic symptoms are predic­tive of later response and remission.³⁹

Dosing strategies
An initial problem with lithium is side effects that emerge when beginning treat­ment, which may discourage the patient and family from using this agent. Starting with 150 mg/d for the first 2 or 3 doses is unlikely to produce any adverse effects and can show the patient that there is a high likelihood that he will be able to tol­erate the medication. Gradual titration over several days—or even weeks—to the target dosage and serum levels will enhance patient compliance. Rate of dos­age increase is best guided by tolerance to the medication. The general consensus is that lithium is most effective at levels of 0.6 to 0.8 mEq/L,⁴⁰ although a lower level (0.5 mEq/L) over a 2-year period also can be effective.⁴¹ Lithium may be used in to treat acute mania at higher serum levels (0.8 to 1.2 mEq/L), however, the acute phase often requires urgent management, usually with an antipsychotic.

Emerging consensus
Although there is a need to gather and analyze longer observational periods to clarify the clinical and biological charac­teristics of persons who respond to lith­ium, there are several points of consensus. Management will be guided by patient characteristics such as age, comorbidities, and other therapies. Most studies that address the effect of lithium level focus on high vs low serum levels. There are 3 cat­egories of lithium serum levels, low (<0.6 mEq/L), mid-range (0.6 to 0.8 mEq/L), and high (>0.8 mEq/L), each has risk-benefit considerations.

The LiTMUS study⁴² compared low-level lithium augmentation with opti­mized personal treatment without lithium. Both groups had similar outcomes but the lithium-treated group had significantly lower use of atypical antipsychotics. This may be important when considering the long-term risk of the metabolic syndrome because the tolerability and side-effect profile of lithium at lower levels is more favorable than that of atypical antipsy­chotics. As lithium levels increase, there seems to be concomitant increase in effi­cacy and side effects. Many patients will benefit with low-level lithium use; yet clearly some individuals require higher dosages for effective maintenance therapy.

Dosing and monitoring. In patients age >50 or those with comorbid medical conditions, use a lower level of lithium (<0.6 mEq/L). Most individuals with BD likely will benefit from the mid-range level strategy (0.6 to 0.8 mEq/L); however, there will be those who require a higher level. When beginning lithium, start at a low dosage (150 mg/d) and increase as tolerated to the desired serum level. With acute mania, temporary use of an antipsychotic will be required.

There are no tests available to determine whether a patient will do well at any of these lithium serum levels. Breakthrough mania in an adherent patient with a serum lithium level of 0.7 mEq/L indicates the need to obtain a higher lithium level. A major deficit in lithium research is the lack of long-term data (>5 years) on out­comes, clinical and biological features with lithium levels because of a lack of pharma­ceutical company support.^3,17 Monitoring mood symptoms using detailed mood charts, whether clinician-administered or self-reported, is an effective way to moni­tor outcomes, provided the clinician uses the same scales or methods to record a patient’s moods. If a patient wants to dis­continue lithium, taper the drug over an extended period (months) to minimize the likelihood of emerging manic or depressive episodes related to drug discontinuation.

Managing side effects
Consider lithium’s side effects in the con­text of their short-, intermediate-, and long-term presence (Table 2). Gradually increasing the lithium dosage often will prevent side effects that manifest in the short term. If side effects emerge at low dosages, proceed slowly with lithium and manage symptoms with other medica­tions. When a patient shows a change in side effects, obtain lithium and electrolytes levels; a change in mental status with con­fusion will require an acute lithium level.

A diary of symptoms or clinically rel­evant matters such as fluid intake or fre­quency of GI- or neurological-related events will help the clinician monitor the frequency and severity of side effects. The patient and clinician should not be dis­couraged by emerging side effects in the short term, because they may dissipate or become minimally intrusive.

Several strategies can alleviate immedi­ate GI effects, such as dosing with meals, enteric-coated formulations, multiple dose strategies, and short-term use of antidiar­rheal medicine as needed. Side effects that disrupt a patient’s fluid and electrolyte balance (diabetes insipidus) to the point of clouding mental status will require discon­tinuing the medication until mental sta­tus improves, then reconsideration of the treatment regime, which will include man­aging diabetes insipidus with amiloride. Managing side effects may require consulta­tion with specialty services. Likewise, some patients might experience neurologic side effects, such as profound tremor, that inter­feres with their ability to function. However, many side effects can be managed symp­tomatically with practical strategies (eg, a sugar-free lozenge for dry mouth or dysgeu­sia). Consider lower lithium dosages and serum levels because patients may experi­ence benefits with lower therapeutic levels.

Long-term side effects include decreased renal function, hypothyroidism, persistent tremor, and dermatologic effects of acne and alopecia. Monitor renal and thyroid function annually in stable patients and more frequently when making changes in the treatment plan.

Before discontinuing lithium, consider discussing the medical issues with a spe­cialist who has experience with complica­tions of lithium.

Bottom Line
Lithium is an effective and under used medication for managing bipolar disorder. Initial prejudices and side effects often deter patients and prescribers from proceeding with a therapeutic trial of lithium. Although the mid-range lithium level of 0.6 to 0.8 mEq/L is desirable, many patients will experience significant benefits with lower levels. Initial strategies include the use of low-dose preparations that are unlikely to have uncomfortable side effects.

Related Resources
• Andreasen A, Ellingrod VL. Lithium-induced diabetes in­sipidus: prevention and management. Current Psychiatry. 2013;12(7):42-45.
• Cipriani A, Hawton K, Stockton S, et al. Lithium in the pre­vention of suicide in mood disorders: updated system­atic review and meta-analysis. BMJ. 2013;346:f3646. doi: 10.1136/bmj.f3646.

Drug Brand Names
Amiloride • Midamor                Lithium • Eskalith, Lithobid

Disclosure
Dr. McInnis reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Lithium is among the most effective therapies for bipolar disorder (BD), and enthusiasm for this simple molecule is waxing. The his­tory of lithium is fascinating,¹ and recent considerations include that this element, the third on the periodic table, has few, if any, indus­try champions. The recent renaissance is caused by a groundswell of appreciation for the clinical efficacy of lithium and an increasing num­ber of providers who are willing to manage patients with lithium.

Target: Bipolar disorder
The target illness for lithium is BD, a spectrum of mood disorders with characteristic features of unstable mood and affect. Shifts in mood include recurrent episodes of mania, which are pathologically ener­gized states with misguided volition and behavior with intoxicating euphoria (or irritability).^₂ Psychomotor activity is elevated and out of character; speech and body movements are revved up, with a dimin­ished need for sleep. The social, personal, and vocational consequences often are disastrous.

The most common mood state of BD is depression. Depressive episodes consist of pathologically compromised energy and volition with a slowing of bodily functions, most prominently cognition and concentration; a pervasive depressed or sad mood is common but not always present. Presence of mixed states, when features of depression and mania are present simultaneously, is one of the many challenges of treating BD; an elevated volitional or energized state may occur with a depressed, dysphoric mood.

Evidence for lithium
Efficacy studies of lithium have focused on managing mood disorders, treating mania and depression, and prevention or main­tenance care.³ Most were performed dur­ing the 1970s and 1980s,³ but recent studies have been comparing lithium with other mood stabilizers^4-7 and searching for a genetic basis for lithium response.^8-10 Other researchers have examined the use of lith­ium to prevent suicide.¹¹ Some have sug­gested a neuroprotective effect of lithium, which may have profound implications for neuropsychiatry if valid.^12-14 Results of additional studies, which are at differ­ent stages of completion, will clarify lith­ium use,^15,16 and characterize the genetic makeup of individuals who respond to lithium.¹⁷ The primary evidence for lith­ium, however, is for maintenance treat­ment of BD and for preventing manic and depressive episodes.

Biochemistry and physiology of lithium. The biochemical and physiological effects of lithium are complex, wide-ranging, and likely to affect hundreds, if not thou­sands, of genes and gene products. The mechanisms of action remain a focus of aca­demic pursuit (for a review of hypotheses related to these mechanisms see Goodwin and Jamison² and Can et al¹⁸) Lithium is involved in cell signaling pathways that involve complex molecular mechanisms of inter- and intracellular communica­tion¹⁹; some neural receptors are down-regulated²⁰ and others show inhibition,²¹ which is thought to be a mechanism of lithium. The hypothesized neuroprotective effect of lithium²² may be mediated through an increased level of brain-derived neuro­trophic factor in brain tissue.¹⁴ Recently, investigators using induced pluripotent stem cell derived neurons have shown that patterns of calcium-related cell signaling in bipolar neurons are affected specifically by lithium in the culture media.²³ There likely are many mechanisms through which lithi­um’s effects are mediated, including a series of dynamic pathways that vary over time and in reaction to the internal and external environments of the cell and person.

The lithium renaissance
In the past decade, there has been an increase in interest and use of lithium because clinicians recognize its efficacy and advantages and can monitor serum levels and gauge the patient’s response and side effects²⁴ against the lithium level. This is important because balancing effi­ cacy and side effects depends on the serum level. Efficacy often is not immediate, although side effects may emerge early. All systems of the body may show effects that could be related to lithium use. It is helpful to be aware of the side effects in chronolog­ical order, because some immediate effects may be associated with starting at higher dosages (Table 1). Common side effects in the short term include:

   • GI distress, such as nausea, vomiting, diarrhea, and abdominal discomfort
   • a fine neurologic tremor, which may be seen with accentuation upon deliber­ate movement
   • prominent thirst with polyuria
   • drowsiness and clouded thinking, which can be upsetting to the patient and family.

In the longer term, adverse effects on kidney and thyroid function are common. Management must include monitoring of the serum level.

Lithium is FDA-approved for acute and maintenance treatment of mania in BD. There are reports that discuss most vari­ants of mood disorders, including BD I, BD II, unipolar depression, rapid cycling, and even alcohol abuse.^25-29 Lithium could help manage mood dysregulation in the context of temperament and personal­ity.³⁰ There is evidence that lithium has an antidepressant effect31-33 and has shown efficacy as an adjunctive treatment for depression.^31-33 There are data that sug­gest that lithium, with its neuroprotective mechanisms, may prevent progression of mild cognitive impairment.³⁴

Is there an ideal lithium candidate?
Mood instability is the characteristic fea­ture of a lithium responder. The instability may be over the course of the day, such as a dysregulated temperament that often is associated with DSM-IV personality cat­egories, shorter-term fluctuations (within days with BD II), or in the context of epi­sodic shifts of mood states over weeks and months, which are characteristic of BD I. The hallmark of mood instability is fluctuation from depression to elevated mood states and charged emotions with increased energy.

The patient considered ideal for lith­ium treatment has BD I with recurrent severe euphoric manic episodes, absence of significant comorbid disorders such as substance abuse, and a family history of lithium response. However, any patient with a clinically significant and unstable mood disorder, regardless of the DSM diagnosis, should be considered for lith­ium treatment.

When considering a lithium trial for a patient with significant mood instability, it is critical to establish the target symptoms and behavior that will help you gauge the efficacy of the intervention. Measurement-based care utilizes clinician and self-report instruments to provide data on the ill­ness course and response to interven­tion. Commonly used clinician driven assessments include the Young Mania Rating Scale³⁵ and the Quick Inventory of Depressive Symptoms,³⁶ while the self-report assessments are the Patient Health Questionnaire³⁷ and the Altman Self- Rating Mania Scale.³⁸

During acute mania or depression, lithium often is used in combination with another medications such as an antipsy­chotic or antidepressant. Used in the out­patient and non-acute setting, lithium may be an “add-on” or monotherapy for pre­venting recurrence of episodes. Response in early acute manic symptoms are predic­tive of later response and remission.³⁹

Dosing strategies
An initial problem with lithium is side effects that emerge when beginning treat­ment, which may discourage the patient and family from using this agent. Starting with 150 mg/d for the first 2 or 3 doses is unlikely to produce any adverse effects and can show the patient that there is a high likelihood that he will be able to tol­erate the medication. Gradual titration over several days—or even weeks—to the target dosage and serum levels will enhance patient compliance. Rate of dos­age increase is best guided by tolerance to the medication. The general consensus is that lithium is most effective at levels of 0.6 to 0.8 mEq/L,⁴⁰ although a lower level (0.5 mEq/L) over a 2-year period also can be effective.⁴¹ Lithium may be used in to treat acute mania at higher serum levels (0.8 to 1.2 mEq/L), however, the acute phase often requires urgent management, usually with an antipsychotic.

Emerging consensus
Although there is a need to gather and analyze longer observational periods to clarify the clinical and biological charac­teristics of persons who respond to lith­ium, there are several points of consensus. Management will be guided by patient characteristics such as age, comorbidities, and other therapies. Most studies that address the effect of lithium level focus on high vs low serum levels. There are 3 cat­egories of lithium serum levels, low (<0.6 mEq/L), mid-range (0.6 to 0.8 mEq/L), and high (>0.8 mEq/L), each has risk-benefit considerations.

The LiTMUS study⁴² compared low-level lithium augmentation with opti­mized personal treatment without lithium. Both groups had similar outcomes but the lithium-treated group had significantly lower use of atypical antipsychotics. This may be important when considering the long-term risk of the metabolic syndrome because the tolerability and side-effect profile of lithium at lower levels is more favorable than that of atypical antipsy­chotics. As lithium levels increase, there seems to be concomitant increase in effi­cacy and side effects. Many patients will benefit with low-level lithium use; yet clearly some individuals require higher dosages for effective maintenance therapy.

Dosing and monitoring. In patients age >50 or those with comorbid medical conditions, use a lower level of lithium (<0.6 mEq/L). Most individuals with BD likely will benefit from the mid-range level strategy (0.6 to 0.8 mEq/L); however, there will be those who require a higher level. When beginning lithium, start at a low dosage (150 mg/d) and increase as tolerated to the desired serum level. With acute mania, temporary use of an antipsychotic will be required.

There are no tests available to determine whether a patient will do well at any of these lithium serum levels. Breakthrough mania in an adherent patient with a serum lithium level of 0.7 mEq/L indicates the need to obtain a higher lithium level. A major deficit in lithium research is the lack of long-term data (>5 years) on out­comes, clinical and biological features with lithium levels because of a lack of pharma­ceutical company support.^3,17 Monitoring mood symptoms using detailed mood charts, whether clinician-administered or self-reported, is an effective way to moni­tor outcomes, provided the clinician uses the same scales or methods to record a patient’s moods. If a patient wants to dis­continue lithium, taper the drug over an extended period (months) to minimize the likelihood of emerging manic or depressive episodes related to drug discontinuation.

Managing side effects
Consider lithium’s side effects in the con­text of their short-, intermediate-, and long-term presence (Table 2). Gradually increasing the lithium dosage often will prevent side effects that manifest in the short term. If side effects emerge at low dosages, proceed slowly with lithium and manage symptoms with other medica­tions. When a patient shows a change in side effects, obtain lithium and electrolytes levels; a change in mental status with con­fusion will require an acute lithium level.

A diary of symptoms or clinically rel­evant matters such as fluid intake or fre­quency of GI- or neurological-related events will help the clinician monitor the frequency and severity of side effects. The patient and clinician should not be dis­couraged by emerging side effects in the short term, because they may dissipate or become minimally intrusive.

Several strategies can alleviate immedi­ate GI effects, such as dosing with meals, enteric-coated formulations, multiple dose strategies, and short-term use of antidiar­rheal medicine as needed. Side effects that disrupt a patient’s fluid and electrolyte balance (diabetes insipidus) to the point of clouding mental status will require discon­tinuing the medication until mental sta­tus improves, then reconsideration of the treatment regime, which will include man­aging diabetes insipidus with amiloride. Managing side effects may require consulta­tion with specialty services. Likewise, some patients might experience neurologic side effects, such as profound tremor, that inter­feres with their ability to function. However, many side effects can be managed symp­tomatically with practical strategies (eg, a sugar-free lozenge for dry mouth or dysgeu­sia). Consider lower lithium dosages and serum levels because patients may experi­ence benefits with lower therapeutic levels.

Long-term side effects include decreased renal function, hypothyroidism, persistent tremor, and dermatologic effects of acne and alopecia. Monitor renal and thyroid function annually in stable patients and more frequently when making changes in the treatment plan.

Before discontinuing lithium, consider discussing the medical issues with a spe­cialist who has experience with complica­tions of lithium.

Bottom Line
Lithium is an effective and under used medication for managing bipolar disorder. Initial prejudices and side effects often deter patients and prescribers from proceeding with a therapeutic trial of lithium. Although the mid-range lithium level of 0.6 to 0.8 mEq/L is desirable, many patients will experience significant benefits with lower levels. Initial strategies include the use of low-dose preparations that are unlikely to have uncomfortable side effects.

Related Resources
• Andreasen A, Ellingrod VL. Lithium-induced diabetes in­sipidus: prevention and management. Current Psychiatry. 2013;12(7):42-45.
• Cipriani A, Hawton K, Stockton S, et al. Lithium in the pre­vention of suicide in mood disorders: updated system­atic review and meta-analysis. BMJ. 2013;346:f3646. doi: 10.1136/bmj.f3646.

Drug Brand Names
Amiloride • Midamor                Lithium • Eskalith, Lithobid

Disclosure
Dr. McInnis reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Lithium is among the most effective therapies for bipolar disorder (BD), and enthusiasm for this simple molecule is waxing. The his­tory of lithium is fascinating,¹ and recent considerations include that this element, the third on the periodic table, has few, if any, indus­try champions. The recent renaissance is caused by a groundswell of appreciation for the clinical efficacy of lithium and an increasing num­ber of providers who are willing to manage patients with lithium.

Target: Bipolar disorder
The target illness for lithium is BD, a spectrum of mood disorders with characteristic features of unstable mood and affect. Shifts in mood include recurrent episodes of mania, which are pathologically ener­gized states with misguided volition and behavior with intoxicating euphoria (or irritability).^₂ Psychomotor activity is elevated and out of character; speech and body movements are revved up, with a dimin­ished need for sleep. The social, personal, and vocational consequences often are disastrous.

The most common mood state of BD is depression. Depressive episodes consist of pathologically compromised energy and volition with a slowing of bodily functions, most prominently cognition and concentration; a pervasive depressed or sad mood is common but not always present. Presence of mixed states, when features of depression and mania are present simultaneously, is one of the many challenges of treating BD; an elevated volitional or energized state may occur with a depressed, dysphoric mood.

Evidence for lithium
Efficacy studies of lithium have focused on managing mood disorders, treating mania and depression, and prevention or main­tenance care.³ Most were performed dur­ing the 1970s and 1980s,³ but recent studies have been comparing lithium with other mood stabilizers^4-7 and searching for a genetic basis for lithium response.^8-10 Other researchers have examined the use of lith­ium to prevent suicide.¹¹ Some have sug­gested a neuroprotective effect of lithium, which may have profound implications for neuropsychiatry if valid.^12-14 Results of additional studies, which are at differ­ent stages of completion, will clarify lith­ium use,^15,16 and characterize the genetic makeup of individuals who respond to lithium.¹⁷ The primary evidence for lith­ium, however, is for maintenance treat­ment of BD and for preventing manic and depressive episodes.

Biochemistry and physiology of lithium. The biochemical and physiological effects of lithium are complex, wide-ranging, and likely to affect hundreds, if not thou­sands, of genes and gene products. The mechanisms of action remain a focus of aca­demic pursuit (for a review of hypotheses related to these mechanisms see Goodwin and Jamison² and Can et al¹⁸) Lithium is involved in cell signaling pathways that involve complex molecular mechanisms of inter- and intracellular communica­tion¹⁹; some neural receptors are down-regulated²⁰ and others show inhibition,²¹ which is thought to be a mechanism of lithium. The hypothesized neuroprotective effect of lithium²² may be mediated through an increased level of brain-derived neuro­trophic factor in brain tissue.¹⁴ Recently, investigators using induced pluripotent stem cell derived neurons have shown that patterns of calcium-related cell signaling in bipolar neurons are affected specifically by lithium in the culture media.²³ There likely are many mechanisms through which lithi­um’s effects are mediated, including a series of dynamic pathways that vary over time and in reaction to the internal and external environments of the cell and person.

The lithium renaissance
In the past decade, there has been an increase in interest and use of lithium because clinicians recognize its efficacy and advantages and can monitor serum levels and gauge the patient’s response and side effects²⁴ against the lithium level. This is important because balancing effi­ cacy and side effects depends on the serum level. Efficacy often is not immediate, although side effects may emerge early. All systems of the body may show effects that could be related to lithium use. It is helpful to be aware of the side effects in chronolog­ical order, because some immediate effects may be associated with starting at higher dosages (Table 1). Common side effects in the short term include:

   • GI distress, such as nausea, vomiting, diarrhea, and abdominal discomfort
   • a fine neurologic tremor, which may be seen with accentuation upon deliber­ate movement
   • prominent thirst with polyuria
   • drowsiness and clouded thinking, which can be upsetting to the patient and family.

In the longer term, adverse effects on kidney and thyroid function are common. Management must include monitoring of the serum level.

Lithium is FDA-approved for acute and maintenance treatment of mania in BD. There are reports that discuss most vari­ants of mood disorders, including BD I, BD II, unipolar depression, rapid cycling, and even alcohol abuse.^25-29 Lithium could help manage mood dysregulation in the context of temperament and personal­ity.³⁰ There is evidence that lithium has an antidepressant effect31-33 and has shown efficacy as an adjunctive treatment for depression.^31-33 There are data that sug­gest that lithium, with its neuroprotective mechanisms, may prevent progression of mild cognitive impairment.³⁴

Is there an ideal lithium candidate?
Mood instability is the characteristic fea­ture of a lithium responder. The instability may be over the course of the day, such as a dysregulated temperament that often is associated with DSM-IV personality cat­egories, shorter-term fluctuations (within days with BD II), or in the context of epi­sodic shifts of mood states over weeks and months, which are characteristic of BD I. The hallmark of mood instability is fluctuation from depression to elevated mood states and charged emotions with increased energy.

The patient considered ideal for lith­ium treatment has BD I with recurrent severe euphoric manic episodes, absence of significant comorbid disorders such as substance abuse, and a family history of lithium response. However, any patient with a clinically significant and unstable mood disorder, regardless of the DSM diagnosis, should be considered for lith­ium treatment.

When considering a lithium trial for a patient with significant mood instability, it is critical to establish the target symptoms and behavior that will help you gauge the efficacy of the intervention. Measurement-based care utilizes clinician and self-report instruments to provide data on the ill­ness course and response to interven­tion. Commonly used clinician driven assessments include the Young Mania Rating Scale³⁵ and the Quick Inventory of Depressive Symptoms,³⁶ while the self-report assessments are the Patient Health Questionnaire³⁷ and the Altman Self- Rating Mania Scale.³⁸

During acute mania or depression, lithium often is used in combination with another medications such as an antipsy­chotic or antidepressant. Used in the out­patient and non-acute setting, lithium may be an “add-on” or monotherapy for pre­venting recurrence of episodes. Response in early acute manic symptoms are predic­tive of later response and remission.³⁹

Dosing strategies
An initial problem with lithium is side effects that emerge when beginning treat­ment, which may discourage the patient and family from using this agent. Starting with 150 mg/d for the first 2 or 3 doses is unlikely to produce any adverse effects and can show the patient that there is a high likelihood that he will be able to tol­erate the medication. Gradual titration over several days—or even weeks—to the target dosage and serum levels will enhance patient compliance. Rate of dos­age increase is best guided by tolerance to the medication. The general consensus is that lithium is most effective at levels of 0.6 to 0.8 mEq/L,⁴⁰ although a lower level (0.5 mEq/L) over a 2-year period also can be effective.⁴¹ Lithium may be used in to treat acute mania at higher serum levels (0.8 to 1.2 mEq/L), however, the acute phase often requires urgent management, usually with an antipsychotic.

Emerging consensus
Although there is a need to gather and analyze longer observational periods to clarify the clinical and biological charac­teristics of persons who respond to lith­ium, there are several points of consensus. Management will be guided by patient characteristics such as age, comorbidities, and other therapies. Most studies that address the effect of lithium level focus on high vs low serum levels. There are 3 cat­egories of lithium serum levels, low (<0.6 mEq/L), mid-range (0.6 to 0.8 mEq/L), and high (>0.8 mEq/L), each has risk-benefit considerations.

The LiTMUS study⁴² compared low-level lithium augmentation with opti­mized personal treatment without lithium. Both groups had similar outcomes but the lithium-treated group had significantly lower use of atypical antipsychotics. This may be important when considering the long-term risk of the metabolic syndrome because the tolerability and side-effect profile of lithium at lower levels is more favorable than that of atypical antipsy­chotics. As lithium levels increase, there seems to be concomitant increase in effi­cacy and side effects. Many patients will benefit with low-level lithium use; yet clearly some individuals require higher dosages for effective maintenance therapy.

Dosing and monitoring. In patients age >50 or those with comorbid medical conditions, use a lower level of lithium (<0.6 mEq/L). Most individuals with BD likely will benefit from the mid-range level strategy (0.6 to 0.8 mEq/L); however, there will be those who require a higher level. When beginning lithium, start at a low dosage (150 mg/d) and increase as tolerated to the desired serum level. With acute mania, temporary use of an antipsychotic will be required.

There are no tests available to determine whether a patient will do well at any of these lithium serum levels. Breakthrough mania in an adherent patient with a serum lithium level of 0.7 mEq/L indicates the need to obtain a higher lithium level. A major deficit in lithium research is the lack of long-term data (>5 years) on out­comes, clinical and biological features with lithium levels because of a lack of pharma­ceutical company support.^3,17 Monitoring mood symptoms using detailed mood charts, whether clinician-administered or self-reported, is an effective way to moni­tor outcomes, provided the clinician uses the same scales or methods to record a patient’s moods. If a patient wants to dis­continue lithium, taper the drug over an extended period (months) to minimize the likelihood of emerging manic or depressive episodes related to drug discontinuation.

Managing side effects
Consider lithium’s side effects in the con­text of their short-, intermediate-, and long-term presence (Table 2). Gradually increasing the lithium dosage often will prevent side effects that manifest in the short term. If side effects emerge at low dosages, proceed slowly with lithium and manage symptoms with other medica­tions. When a patient shows a change in side effects, obtain lithium and electrolytes levels; a change in mental status with con­fusion will require an acute lithium level.

A diary of symptoms or clinically rel­evant matters such as fluid intake or fre­quency of GI- or neurological-related events will help the clinician monitor the frequency and severity of side effects. The patient and clinician should not be dis­couraged by emerging side effects in the short term, because they may dissipate or become minimally intrusive.

Several strategies can alleviate immedi­ate GI effects, such as dosing with meals, enteric-coated formulations, multiple dose strategies, and short-term use of antidiar­rheal medicine as needed. Side effects that disrupt a patient’s fluid and electrolyte balance (diabetes insipidus) to the point of clouding mental status will require discon­tinuing the medication until mental sta­tus improves, then reconsideration of the treatment regime, which will include man­aging diabetes insipidus with amiloride. Managing side effects may require consulta­tion with specialty services. Likewise, some patients might experience neurologic side effects, such as profound tremor, that inter­feres with their ability to function. However, many side effects can be managed symp­tomatically with practical strategies (eg, a sugar-free lozenge for dry mouth or dysgeu­sia). Consider lower lithium dosages and serum levels because patients may experi­ence benefits with lower therapeutic levels.

Long-term side effects include decreased renal function, hypothyroidism, persistent tremor, and dermatologic effects of acne and alopecia. Monitor renal and thyroid function annually in stable patients and more frequently when making changes in the treatment plan.

Before discontinuing lithium, consider discussing the medical issues with a spe­cialist who has experience with complica­tions of lithium.

Bottom Line
Lithium is an effective and under used medication for managing bipolar disorder. Initial prejudices and side effects often deter patients and prescribers from proceeding with a therapeutic trial of lithium. Although the mid-range lithium level of 0.6 to 0.8 mEq/L is desirable, many patients will experience significant benefits with lower levels. Initial strategies include the use of low-dose preparations that are unlikely to have uncomfortable side effects.

Related Resources
• Andreasen A, Ellingrod VL. Lithium-induced diabetes in­sipidus: prevention and management. Current Psychiatry. 2013;12(7):42-45.
• Cipriani A, Hawton K, Stockton S, et al. Lithium in the pre­vention of suicide in mood disorders: updated system­atic review and meta-analysis. BMJ. 2013;346:f3646. doi: 10.1136/bmj.f3646.

Drug Brand Names
Amiloride • Midamor                Lithium • Eskalith, Lithobid

Disclosure
Dr. McInnis reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

I might have a jaundiced view of prog­ress but, across most medical special­ties, diseases are still managed, not cured. Chronicity is almost ubiquitous among medical ailments, and no specialty can boast that it restores function com­pletely and fully restores patients’ qual­ity of life.

Psychiatry has had its share of missteps
Prefrontal lobotomy is perhaps the most infamous of many discredited treatments that were introduced as a great solution to severe brain disor­ders such as schizophrenia.¹ Prefrontal lobotomy (leucotomy) was initially heralded as a major medical advance in 1935; its originator, neurosurgeon António Egas Moniz, shared the Nobel Prize in Medicine or Physiology in 1949 for what is now regarded as may­hem. Prefrontal lobotomy was widely used for many conditions—not just for psychosis—but it fell from favor rapidly after the discovery of anti-psychotic drugs.

A similar fate befell other treatments that were introduced to psychiatry:
   • malaria therapy (1917) for gen­eral paresis of the insane (the condi­tion was later recognized as tertiary syphilis)
   • deep sleep therapy (1920) for schizophrenia
   • insulin shock therapy (1933), also for schizophrenia.

Those discredited therapies were lauded as significant advances, only to be shunned later as harmful, even barbaric.

Treating addiction is another saga of false steps. Fifty-nine different treat­ments for addiction have been intro­duced over the past few decades, many later discredited as “psychoquackery.”² In the breathless rush to cure desperate conditions, there often is the risk that pseudoscience will masquerade as sci­ence. Many patients suffer needlessly before the medical community exam­ines the accumulated evidence and dis­credits useless or harmful treatments.

Psychiatry isn’t alone in lacking cures
A fitting slogan of many non-psychiatric medical specialties is “to treat, perchance to cure.” Consider some examples:
   • In cardiology, congestive heart fail­ure, a chronic illness, is managed but rarely cured, and leads to early mortality.
   • Nephrologists struggle to maintain a semblance of kidney function in renal failure patients, before placing them on the long waiting list for a kidney transplant.
   • Gastroenterologists can only hope to maintain liver function in severe hep­atitis, or to alleviate the misery of ulcer­ative colitis.
   • Rheumatologists do what they can to relieve the debilitating symptoms of rheumatoid arthritis, systemic lupus erythematosus, and Sjögren’s syndrome.
   • Pulmonologists know they can never restore normal lung function for their patients with chronic obstructive pulmonary disease; they can only help them hang on with partial function.
   • Oncologists valiantly fight aggres­sive cancers with the hope of prolonging life for a few months or years.
   • Neurologists valiantly try to manage multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, epilepsy, stroke, myasthenia gravis, and amyotrophic lat­eral sclerosis—often with limited, if any, success at achieving remission.

Internal medicine has had its share of discredited therapies, too—ones that were withdrawn because they caused harm or were of dubious or inconclu­sive efficacy.³ Thanks to careful analy­sis of the efficacy and safety of medical procedures introduced during the past decade, we know that 40% of 146 pro­cedures examined were eventually dis­credited and withdrawn. (That kind of analysis should be undertaken in psychotherapy, where evidence-based therapies can be counted on one hand but dozens more are promoted as legiti­mate.⁴ Psychotherapy can be harmful.⁵)

As with patients in psychiatry, patients of all these specialties are at risk of suffering disruptive iatrogenic side effects that, at times, approach torture—just to have progression of disease halted but not necessarily to deliver full remission. The quality of life for patients who have a chronic disease ranges from barely tolerable to poor, but is rarely good or optimal—and that is the case across all of medicine, includ­ing psychiatry.

Desperation often drives dubious innovation
There are numerous “desperate” dis­eases across all medical specialties, including psychiatry. Radical and harm­ful measures are sometimes proposed and marketed to treat many of those conditions; more often, useless, ineffec­tive, futile “treatments” are introduced, and it might take years before they are discredited and withdrawn.^6,7 Useless treatments can be harmful, too, because they delay the use of potentially effective procedures.

Move forward with caution!
What does this brief look at the missteps of medicine tell us? First, medical prog­ress is like the mambo: We take steps forward but then step backward again; and, as Karl Popper noted, science learns more from its failures than from its suc­cesses.⁸ Second, all physicians must be judicious and guided by evidence when they select treatments.

For your patients’ sake, choose wisely!⁹

I might have a jaundiced view of prog­ress but, across most medical special­ties, diseases are still managed, not cured. Chronicity is almost ubiquitous among medical ailments, and no specialty can boast that it restores function com­pletely and fully restores patients’ qual­ity of life.

Psychiatry has had its share of missteps
Prefrontal lobotomy is perhaps the most infamous of many discredited treatments that were introduced as a great solution to severe brain disor­ders such as schizophrenia.¹ Prefrontal lobotomy (leucotomy) was initially heralded as a major medical advance in 1935; its originator, neurosurgeon António Egas Moniz, shared the Nobel Prize in Medicine or Physiology in 1949 for what is now regarded as may­hem. Prefrontal lobotomy was widely used for many conditions—not just for psychosis—but it fell from favor rapidly after the discovery of anti-psychotic drugs.

A similar fate befell other treatments that were introduced to psychiatry:
   • malaria therapy (1917) for gen­eral paresis of the insane (the condi­tion was later recognized as tertiary syphilis)
   • deep sleep therapy (1920) for schizophrenia
   • insulin shock therapy (1933), also for schizophrenia.

Those discredited therapies were lauded as significant advances, only to be shunned later as harmful, even barbaric.

Treating addiction is another saga of false steps. Fifty-nine different treat­ments for addiction have been intro­duced over the past few decades, many later discredited as “psychoquackery.”² In the breathless rush to cure desperate conditions, there often is the risk that pseudoscience will masquerade as sci­ence. Many patients suffer needlessly before the medical community exam­ines the accumulated evidence and dis­credits useless or harmful treatments.

Psychiatry isn’t alone in lacking cures
A fitting slogan of many non-psychiatric medical specialties is “to treat, perchance to cure.” Consider some examples:
   • In cardiology, congestive heart fail­ure, a chronic illness, is managed but rarely cured, and leads to early mortality.
   • Nephrologists struggle to maintain a semblance of kidney function in renal failure patients, before placing them on the long waiting list for a kidney transplant.
   • Gastroenterologists can only hope to maintain liver function in severe hep­atitis, or to alleviate the misery of ulcer­ative colitis.
   • Rheumatologists do what they can to relieve the debilitating symptoms of rheumatoid arthritis, systemic lupus erythematosus, and Sjögren’s syndrome.
   • Pulmonologists know they can never restore normal lung function for their patients with chronic obstructive pulmonary disease; they can only help them hang on with partial function.
   • Oncologists valiantly fight aggres­sive cancers with the hope of prolonging life for a few months or years.
   • Neurologists valiantly try to manage multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, epilepsy, stroke, myasthenia gravis, and amyotrophic lat­eral sclerosis—often with limited, if any, success at achieving remission.

Internal medicine has had its share of discredited therapies, too—ones that were withdrawn because they caused harm or were of dubious or inconclu­sive efficacy.³ Thanks to careful analy­sis of the efficacy and safety of medical procedures introduced during the past decade, we know that 40% of 146 pro­cedures examined were eventually dis­credited and withdrawn. (That kind of analysis should be undertaken in psychotherapy, where evidence-based therapies can be counted on one hand but dozens more are promoted as legiti­mate.⁴ Psychotherapy can be harmful.⁵)

As with patients in psychiatry, patients of all these specialties are at risk of suffering disruptive iatrogenic side effects that, at times, approach torture—just to have progression of disease halted but not necessarily to deliver full remission. The quality of life for patients who have a chronic disease ranges from barely tolerable to poor, but is rarely good or optimal—and that is the case across all of medicine, includ­ing psychiatry.

Desperation often drives dubious innovation
There are numerous “desperate” dis­eases across all medical specialties, including psychiatry. Radical and harm­ful measures are sometimes proposed and marketed to treat many of those conditions; more often, useless, ineffec­tive, futile “treatments” are introduced, and it might take years before they are discredited and withdrawn.^6,7 Useless treatments can be harmful, too, because they delay the use of potentially effective procedures.

Move forward with caution!
What does this brief look at the missteps of medicine tell us? First, medical prog­ress is like the mambo: We take steps forward but then step backward again; and, as Karl Popper noted, science learns more from its failures than from its suc­cesses.⁸ Second, all physicians must be judicious and guided by evidence when they select treatments.

For your patients’ sake, choose wisely!⁹

I might have a jaundiced view of prog­ress but, across most medical special­ties, diseases are still managed, not cured. Chronicity is almost ubiquitous among medical ailments, and no specialty can boast that it restores function com­pletely and fully restores patients’ qual­ity of life.

Psychiatry has had its share of missteps
Prefrontal lobotomy is perhaps the most infamous of many discredited treatments that were introduced as a great solution to severe brain disor­ders such as schizophrenia.¹ Prefrontal lobotomy (leucotomy) was initially heralded as a major medical advance in 1935; its originator, neurosurgeon António Egas Moniz, shared the Nobel Prize in Medicine or Physiology in 1949 for what is now regarded as may­hem. Prefrontal lobotomy was widely used for many conditions—not just for psychosis—but it fell from favor rapidly after the discovery of anti-psychotic drugs.

A similar fate befell other treatments that were introduced to psychiatry:
   • malaria therapy (1917) for gen­eral paresis of the insane (the condi­tion was later recognized as tertiary syphilis)
   • deep sleep therapy (1920) for schizophrenia
   • insulin shock therapy (1933), also for schizophrenia.

Those discredited therapies were lauded as significant advances, only to be shunned later as harmful, even barbaric.

Treating addiction is another saga of false steps. Fifty-nine different treat­ments for addiction have been intro­duced over the past few decades, many later discredited as “psychoquackery.”² In the breathless rush to cure desperate conditions, there often is the risk that pseudoscience will masquerade as sci­ence. Many patients suffer needlessly before the medical community exam­ines the accumulated evidence and dis­credits useless or harmful treatments.

Psychiatry isn’t alone in lacking cures
A fitting slogan of many non-psychiatric medical specialties is “to treat, perchance to cure.” Consider some examples:
   • In cardiology, congestive heart fail­ure, a chronic illness, is managed but rarely cured, and leads to early mortality.
   • Nephrologists struggle to maintain a semblance of kidney function in renal failure patients, before placing them on the long waiting list for a kidney transplant.
   • Gastroenterologists can only hope to maintain liver function in severe hep­atitis, or to alleviate the misery of ulcer­ative colitis.
   • Rheumatologists do what they can to relieve the debilitating symptoms of rheumatoid arthritis, systemic lupus erythematosus, and Sjögren’s syndrome.
   • Pulmonologists know they can never restore normal lung function for their patients with chronic obstructive pulmonary disease; they can only help them hang on with partial function.
   • Oncologists valiantly fight aggres­sive cancers with the hope of prolonging life for a few months or years.
   • Neurologists valiantly try to manage multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, epilepsy, stroke, myasthenia gravis, and amyotrophic lat­eral sclerosis—often with limited, if any, success at achieving remission.

Internal medicine has had its share of discredited therapies, too—ones that were withdrawn because they caused harm or were of dubious or inconclu­sive efficacy.³ Thanks to careful analy­sis of the efficacy and safety of medical procedures introduced during the past decade, we know that 40% of 146 pro­cedures examined were eventually dis­credited and withdrawn. (That kind of analysis should be undertaken in psychotherapy, where evidence-based therapies can be counted on one hand but dozens more are promoted as legiti­mate.⁴ Psychotherapy can be harmful.⁵)

As with patients in psychiatry, patients of all these specialties are at risk of suffering disruptive iatrogenic side effects that, at times, approach torture—just to have progression of disease halted but not necessarily to deliver full remission. The quality of life for patients who have a chronic disease ranges from barely tolerable to poor, but is rarely good or optimal—and that is the case across all of medicine, includ­ing psychiatry.

Desperation often drives dubious innovation
There are numerous “desperate” dis­eases across all medical specialties, including psychiatry. Radical and harm­ful measures are sometimes proposed and marketed to treat many of those conditions; more often, useless, ineffec­tive, futile “treatments” are introduced, and it might take years before they are discredited and withdrawn.^6,7 Useless treatments can be harmful, too, because they delay the use of potentially effective procedures.

Move forward with caution!
What does this brief look at the missteps of medicine tell us? First, medical prog­ress is like the mambo: We take steps forward but then step backward again; and, as Karl Popper noted, science learns more from its failures than from its suc­cesses.⁸ Second, all physicians must be judicious and guided by evidence when they select treatments.

For your patients’ sake, choose wisely!⁹

Many patients experience difficulty swallowing pills, for various reasons:

• discomfort (particularly pediatric and geriatric patients)
• postsurgical need for an alternate route of enteral intake (nasogastric tube, gas­trostomy, jejunostomy)
• dysphagia due to a neurologic disorder (multiple sclerosis, impaired gag reflex, dementing processes)
• odynophagia (pain upon swallowing) due to gastroesophageal reflux or a structural abnormality
• a structural abnormality of the head or neck that impairs swallowing.¹

If these difficulties are not addressed, they can interfere with medication adherence. In those instances, using an alternative dosage form or manip­ulating an available formulation might be required.

Crushing guidelines
There are limited data on crushed-form prod­ucts and their impact on efficacy. Therefore, when patients have difficulty taking pills, switching to liquid solution or orally disin­tegrating forms is recommended. However, most psychotropics are available only as tablets or capsules. Patients can crush their pills immediately before administration for easier intake. The following are some general guidelines for doing so:²

• Scored tablets typically can be crushed.
• Crushing sublingual and buccal tablets can alter their effectiveness.
• Crushing sustained-release medi­cations can eliminate the sustained-release action.³
• Enteric-coated medications should not be crushed, because this can alter drug absorption.
• Capsules can generally be opened to administer powdered contents, unless the capsule has time-release properties or an enteric coating.

The accompanying Table, organized by drug class, indicates whether a drug can be crushed to a powdered form, which usu­ally is mixed with food or liquid for easier intake. The Table also lists liquid and orally disintegrating forms available, and other routes, including injectable immediate and long-acting formulations. Helping patients find a medication formulation that suits their needs strengthens adherence and the therapeutic relationship.

Many patients experience difficulty swallowing pills, for various reasons:

• discomfort (particularly pediatric and geriatric patients)
• postsurgical need for an alternate route of enteral intake (nasogastric tube, gas­trostomy, jejunostomy)
• dysphagia due to a neurologic disorder (multiple sclerosis, impaired gag reflex, dementing processes)
• odynophagia (pain upon swallowing) due to gastroesophageal reflux or a structural abnormality
• a structural abnormality of the head or neck that impairs swallowing.¹

If these difficulties are not addressed, they can interfere with medication adherence. In those instances, using an alternative dosage form or manip­ulating an available formulation might be required.

Crushing guidelines
There are limited data on crushed-form prod­ucts and their impact on efficacy. Therefore, when patients have difficulty taking pills, switching to liquid solution or orally disin­tegrating forms is recommended. However, most psychotropics are available only as tablets or capsules. Patients can crush their pills immediately before administration for easier intake. The following are some general guidelines for doing so:²

• Scored tablets typically can be crushed.
• Crushing sublingual and buccal tablets can alter their effectiveness.
• Crushing sustained-release medi­cations can eliminate the sustained-release action.³
• Enteric-coated medications should not be crushed, because this can alter drug absorption.
• Capsules can generally be opened to administer powdered contents, unless the capsule has time-release properties or an enteric coating.

The accompanying Table, organized by drug class, indicates whether a drug can be crushed to a powdered form, which usu­ally is mixed with food or liquid for easier intake. The Table also lists liquid and orally disintegrating forms available, and other routes, including injectable immediate and long-acting formulations. Helping patients find a medication formulation that suits their needs strengthens adherence and the therapeutic relationship.

Many patients experience difficulty swallowing pills, for various reasons:

• discomfort (particularly pediatric and geriatric patients)
• postsurgical need for an alternate route of enteral intake (nasogastric tube, gas­trostomy, jejunostomy)
• dysphagia due to a neurologic disorder (multiple sclerosis, impaired gag reflex, dementing processes)
• odynophagia (pain upon swallowing) due to gastroesophageal reflux or a structural abnormality
• a structural abnormality of the head or neck that impairs swallowing.¹

If these difficulties are not addressed, they can interfere with medication adherence. In those instances, using an alternative dosage form or manip­ulating an available formulation might be required.

Crushing guidelines
There are limited data on crushed-form prod­ucts and their impact on efficacy. Therefore, when patients have difficulty taking pills, switching to liquid solution or orally disin­tegrating forms is recommended. However, most psychotropics are available only as tablets or capsules. Patients can crush their pills immediately before administration for easier intake. The following are some general guidelines for doing so:²

• Scored tablets typically can be crushed.
• Crushing sublingual and buccal tablets can alter their effectiveness.
• Crushing sustained-release medi­cations can eliminate the sustained-release action.³
• Enteric-coated medications should not be crushed, because this can alter drug absorption.
• Capsules can generally be opened to administer powdered contents, unless the capsule has time-release properties or an enteric coating.

The accompanying Table, organized by drug class, indicates whether a drug can be crushed to a powdered form, which usu­ally is mixed with food or liquid for easier intake. The Table also lists liquid and orally disintegrating forms available, and other routes, including injectable immediate and long-acting formulations. Helping patients find a medication formulation that suits their needs strengthens adherence and the therapeutic relationship.

Mr. D, age 30, has a 12-year history of schizophrenia and is experiencing worsening auditory hallucinations despite reported medication adherence. He has been taking clozapine, maintenance dos­ages 500 to 700 mg/d, for 4 years and smokes 2 packs of cigarettes a day. When Mr. D is admitted to a nonsmoking inpatient psychi­atric facility, he receives nicotine transdermal patches, 21 mg/d, for nicotine withdrawal. Mr. D’s most recent outpatient clozapine dosage, 700 mg/d, is resumed. All laboratory tests, including complete blood count with differen­tial, are within normal limits at admission.

Five days later Mr. D is tachycardic with a heart rate of 109 beats per minute. When assessing Mr. D, we notice he has alogia and that, when he does speak, his speech is slowed with a 4 to 5 second delay in response. He also appears sedated. We observe occasional mild jerking of his shoul­der and lower legs.

Mr. D reports that his auditory hallucina­tions have lessened since his admission, but complains of difficulty remembering infor­mation and feeling tired during the day. The treatment team suspects clozapine toxicity; his trough clozapine level is 1,350 ng/mL (therapeutic range, 350 to 1,000 ng/mL).

It is well documented that cigarette smoke can induce cytochrome P450 (CYP) isoenzymes, specifically CYP1A1, CYP1A2, and CYP2E1. Because clozapine is primarily metabolized by CYP1A2 (approximately 70%), smoking can induce clozapine metabolism and abruptly stopping smoking can increase clozapine levels.¹ The polycyclic aromatic hydrocarbons, not the nicotine, found in cigarettes are thought to be responsible for CYP1A2 induction; therefore, use of a nicotine replacement product did not prevent the increase in Mr. D’s clozapine levels.
 

Examining the evidence

Meyer¹ evaluated clozapine levels before and after implementation of a hospital-wide smoking ban (N = 11). Clozapine dosages were not adjusted at the time of the smoking ban, which resulted in a mean 72% increase in clozapine levels after a min­imum of 2 weeks as nonsmokers. Even after eliminating 2 outliers, the mean increase in clozapine levels was 36.1%. Murayama-Sung et al² reported a statistically signifi­cant increase in the level of clozapine (46%, P = .004) and the level of norclozapine (23%, P = .02) after a hospital-wide smoking ban was instituted (N = 14). However, the pre-change and post-change in the ratio of clo­zapine to norclozapine level was not found to be statistically significant. Haslemo et al³ found that smoking as few as 7 to 12 cigarettes a day was sufficient for maximum induction of CYP1A2. Because Mr. D was smoking 2 packs of cigarettes a day (40 cigarettes) with an clozapine dosage 700 mg/d as an outpatient, he likely expe­rienced significant induction of clozapine metabolism through CYP1A2, which was no longer present when he stopped smoking.

Therapeutic clozapine concentrations are typically above 350 and 420 ng/mL.⁴ Concentrations >700 ng/mL are associ­ated with increased adverse effects, but generally are not associated with a higher response; levels >900 ng/mL have been associated with toxicity.⁴ Clozapine-treated patients on a stable dosage who smoke can experience clozapine-related adverse effects after admission to a smoke-free facility secondary to an increase in the clozapine concentration (Table 1).⁴

Faber and Fuhr⁶ recommended reduc­ing the dosage of a CYP1A2 substrate medication, such as clozapine, olanzap­ine, or theophylline, by 10% each day until the dosage has been reduced by 40% in patients who stop smoking. Lowe and Ackman⁵ proposed reducing the clozapine dosage by 30% to 40% to achieve a pre-cessation serum concentration at 1 week. For Mr. D, this would mean decreasing the clozapine dosage to 425 to 500 mg/d.

Assuming that Mr. D’s clozapine dosage is decreased during his hospitalization and that he resumes smoking after discharge, it is likely the dosage will need to be increased. It may take several weeks to see maximal induction, because new CYP enzymes need to be synthesized when the patient resumes smoking.⁷ One recommendation is to increase the clozapine dosage by a factor of 1.5 over 2 to 4 weeks, with close monitoring of the clozapine concentration and adverse effects because this increase is approximate.⁷ Depending on when Mr. D’s follow-up appointment is scheduled, the practitioner may need to plan a dosage adjustment to prevent a decrease in his clozapine level caused by smoking to prevent a worsening of symptoms and rehospitalization.

This case emphasizes the importance of asking clozapine-treated patients about their smoking history when they are admit­ted to a smoke-free facility. For several reasons, >60% of patients with schizophre­nia smoke cigarettes⁸ (Table 2).^9-14 Patients who smoke and are on a stable dosage of clozapine might require a dos­age reduction when they are admitted to a smoke-free facility to avoid adverse effects. If the dosage is not adjusted, a patient may experience clozapine-induced adverse effects, such as tachycardia, sedation, and seizures. It is likely that patients such as Mr. D will experience fluctuation in the clo­zapine level and possibly changes in effi­cacy and tolerability transitioning between inpatient and outpatient settings if the dos­age is not adjusted.

Drug Brand Names
Clozapine • Clozaril             Theophylline • Theo-Dur
Olanzapine • Zyprexa

Disclosure
The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Mr. D, age 30, has a 12-year history of schizophrenia and is experiencing worsening auditory hallucinations despite reported medication adherence. He has been taking clozapine, maintenance dos­ages 500 to 700 mg/d, for 4 years and smokes 2 packs of cigarettes a day. When Mr. D is admitted to a nonsmoking inpatient psychi­atric facility, he receives nicotine transdermal patches, 21 mg/d, for nicotine withdrawal. Mr. D’s most recent outpatient clozapine dosage, 700 mg/d, is resumed. All laboratory tests, including complete blood count with differen­tial, are within normal limits at admission.

Five days later Mr. D is tachycardic with a heart rate of 109 beats per minute. When assessing Mr. D, we notice he has alogia and that, when he does speak, his speech is slowed with a 4 to 5 second delay in response. He also appears sedated. We observe occasional mild jerking of his shoul­der and lower legs.

Mr. D reports that his auditory hallucina­tions have lessened since his admission, but complains of difficulty remembering infor­mation and feeling tired during the day. The treatment team suspects clozapine toxicity; his trough clozapine level is 1,350 ng/mL (therapeutic range, 350 to 1,000 ng/mL).

It is well documented that cigarette smoke can induce cytochrome P450 (CYP) isoenzymes, specifically CYP1A1, CYP1A2, and CYP2E1. Because clozapine is primarily metabolized by CYP1A2 (approximately 70%), smoking can induce clozapine metabolism and abruptly stopping smoking can increase clozapine levels.¹ The polycyclic aromatic hydrocarbons, not the nicotine, found in cigarettes are thought to be responsible for CYP1A2 induction; therefore, use of a nicotine replacement product did not prevent the increase in Mr. D’s clozapine levels.
 

Examining the evidence

Meyer¹ evaluated clozapine levels before and after implementation of a hospital-wide smoking ban (N = 11). Clozapine dosages were not adjusted at the time of the smoking ban, which resulted in a mean 72% increase in clozapine levels after a min­imum of 2 weeks as nonsmokers. Even after eliminating 2 outliers, the mean increase in clozapine levels was 36.1%. Murayama-Sung et al² reported a statistically signifi­cant increase in the level of clozapine (46%, P = .004) and the level of norclozapine (23%, P = .02) after a hospital-wide smoking ban was instituted (N = 14). However, the pre-change and post-change in the ratio of clo­zapine to norclozapine level was not found to be statistically significant. Haslemo et al³ found that smoking as few as 7 to 12 cigarettes a day was sufficient for maximum induction of CYP1A2. Because Mr. D was smoking 2 packs of cigarettes a day (40 cigarettes) with an clozapine dosage 700 mg/d as an outpatient, he likely expe­rienced significant induction of clozapine metabolism through CYP1A2, which was no longer present when he stopped smoking.

Therapeutic clozapine concentrations are typically above 350 and 420 ng/mL.⁴ Concentrations >700 ng/mL are associ­ated with increased adverse effects, but generally are not associated with a higher response; levels >900 ng/mL have been associated with toxicity.⁴ Clozapine-treated patients on a stable dosage who smoke can experience clozapine-related adverse effects after admission to a smoke-free facility secondary to an increase in the clozapine concentration (Table 1).⁴

Faber and Fuhr⁶ recommended reduc­ing the dosage of a CYP1A2 substrate medication, such as clozapine, olanzap­ine, or theophylline, by 10% each day until the dosage has been reduced by 40% in patients who stop smoking. Lowe and Ackman⁵ proposed reducing the clozapine dosage by 30% to 40% to achieve a pre-cessation serum concentration at 1 week. For Mr. D, this would mean decreasing the clozapine dosage to 425 to 500 mg/d.

Assuming that Mr. D’s clozapine dosage is decreased during his hospitalization and that he resumes smoking after discharge, it is likely the dosage will need to be increased. It may take several weeks to see maximal induction, because new CYP enzymes need to be synthesized when the patient resumes smoking.⁷ One recommendation is to increase the clozapine dosage by a factor of 1.5 over 2 to 4 weeks, with close monitoring of the clozapine concentration and adverse effects because this increase is approximate.⁷ Depending on when Mr. D’s follow-up appointment is scheduled, the practitioner may need to plan a dosage adjustment to prevent a decrease in his clozapine level caused by smoking to prevent a worsening of symptoms and rehospitalization.

This case emphasizes the importance of asking clozapine-treated patients about their smoking history when they are admit­ted to a smoke-free facility. For several reasons, >60% of patients with schizophre­nia smoke cigarettes⁸ (Table 2).^9-14 Patients who smoke and are on a stable dosage of clozapine might require a dos­age reduction when they are admitted to a smoke-free facility to avoid adverse effects. If the dosage is not adjusted, a patient may experience clozapine-induced adverse effects, such as tachycardia, sedation, and seizures. It is likely that patients such as Mr. D will experience fluctuation in the clo­zapine level and possibly changes in effi­cacy and tolerability transitioning between inpatient and outpatient settings if the dos­age is not adjusted.

Drug Brand Names
Clozapine • Clozaril             Theophylline • Theo-Dur
Olanzapine • Zyprexa

Disclosure
The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Mr. D, age 30, has a 12-year history of schizophrenia and is experiencing worsening auditory hallucinations despite reported medication adherence. He has been taking clozapine, maintenance dos­ages 500 to 700 mg/d, for 4 years and smokes 2 packs of cigarettes a day. When Mr. D is admitted to a nonsmoking inpatient psychi­atric facility, he receives nicotine transdermal patches, 21 mg/d, for nicotine withdrawal. Mr. D’s most recent outpatient clozapine dosage, 700 mg/d, is resumed. All laboratory tests, including complete blood count with differen­tial, are within normal limits at admission.

Five days later Mr. D is tachycardic with a heart rate of 109 beats per minute. When assessing Mr. D, we notice he has alogia and that, when he does speak, his speech is slowed with a 4 to 5 second delay in response. He also appears sedated. We observe occasional mild jerking of his shoul­der and lower legs.

Mr. D reports that his auditory hallucina­tions have lessened since his admission, but complains of difficulty remembering infor­mation and feeling tired during the day. The treatment team suspects clozapine toxicity; his trough clozapine level is 1,350 ng/mL (therapeutic range, 350 to 1,000 ng/mL).

It is well documented that cigarette smoke can induce cytochrome P450 (CYP) isoenzymes, specifically CYP1A1, CYP1A2, and CYP2E1. Because clozapine is primarily metabolized by CYP1A2 (approximately 70%), smoking can induce clozapine metabolism and abruptly stopping smoking can increase clozapine levels.¹ The polycyclic aromatic hydrocarbons, not the nicotine, found in cigarettes are thought to be responsible for CYP1A2 induction; therefore, use of a nicotine replacement product did not prevent the increase in Mr. D’s clozapine levels.
 

Examining the evidence

Meyer¹ evaluated clozapine levels before and after implementation of a hospital-wide smoking ban (N = 11). Clozapine dosages were not adjusted at the time of the smoking ban, which resulted in a mean 72% increase in clozapine levels after a min­imum of 2 weeks as nonsmokers. Even after eliminating 2 outliers, the mean increase in clozapine levels was 36.1%. Murayama-Sung et al² reported a statistically signifi­cant increase in the level of clozapine (46%, P = .004) and the level of norclozapine (23%, P = .02) after a hospital-wide smoking ban was instituted (N = 14). However, the pre-change and post-change in the ratio of clo­zapine to norclozapine level was not found to be statistically significant. Haslemo et al³ found that smoking as few as 7 to 12 cigarettes a day was sufficient for maximum induction of CYP1A2. Because Mr. D was smoking 2 packs of cigarettes a day (40 cigarettes) with an clozapine dosage 700 mg/d as an outpatient, he likely expe­rienced significant induction of clozapine metabolism through CYP1A2, which was no longer present when he stopped smoking.

Therapeutic clozapine concentrations are typically above 350 and 420 ng/mL.⁴ Concentrations >700 ng/mL are associ­ated with increased adverse effects, but generally are not associated with a higher response; levels >900 ng/mL have been associated with toxicity.⁴ Clozapine-treated patients on a stable dosage who smoke can experience clozapine-related adverse effects after admission to a smoke-free facility secondary to an increase in the clozapine concentration (Table 1).⁴

Faber and Fuhr⁶ recommended reduc­ing the dosage of a CYP1A2 substrate medication, such as clozapine, olanzap­ine, or theophylline, by 10% each day until the dosage has been reduced by 40% in patients who stop smoking. Lowe and Ackman⁵ proposed reducing the clozapine dosage by 30% to 40% to achieve a pre-cessation serum concentration at 1 week. For Mr. D, this would mean decreasing the clozapine dosage to 425 to 500 mg/d.

Assuming that Mr. D’s clozapine dosage is decreased during his hospitalization and that he resumes smoking after discharge, it is likely the dosage will need to be increased. It may take several weeks to see maximal induction, because new CYP enzymes need to be synthesized when the patient resumes smoking.⁷ One recommendation is to increase the clozapine dosage by a factor of 1.5 over 2 to 4 weeks, with close monitoring of the clozapine concentration and adverse effects because this increase is approximate.⁷ Depending on when Mr. D’s follow-up appointment is scheduled, the practitioner may need to plan a dosage adjustment to prevent a decrease in his clozapine level caused by smoking to prevent a worsening of symptoms and rehospitalization.

This case emphasizes the importance of asking clozapine-treated patients about their smoking history when they are admit­ted to a smoke-free facility. For several reasons, >60% of patients with schizophre­nia smoke cigarettes⁸ (Table 2).^9-14 Patients who smoke and are on a stable dosage of clozapine might require a dos­age reduction when they are admitted to a smoke-free facility to avoid adverse effects. If the dosage is not adjusted, a patient may experience clozapine-induced adverse effects, such as tachycardia, sedation, and seizures. It is likely that patients such as Mr. D will experience fluctuation in the clo­zapine level and possibly changes in effi­cacy and tolerability transitioning between inpatient and outpatient settings if the dos­age is not adjusted.

Drug Brand Names
Clozapine • Clozaril             Theophylline • Theo-Dur
Olanzapine • Zyprexa

Disclosure
The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Depression—sad, empty, or irritable mood accompanied by somatic or cognitive changes—is not a homoge­neous condition. Recognizing subtypes of depressive illness can guide treatment and relieve your patient’s suf­fering. In this 2-part article [April and May 2014 issues], I summarize information about clinically distinct subtypes of depression, as they are recognized within diagnostic systems or as descriptors of treatment outcomes for particular sub­groups of patients. My focus is on practical considerations for assessing and managing depression. Because many forms of the disorder respond inadequately to initial antidepressant treatment, optimal “next-step” pharmacotherapy, after nonre­sponse or partial response, often hinges on clinical subtyping.

The second part of this article examines “situational,” treat­ment-resistant, melancholic, agitated, anxious, and atypical depression; depression occurring with a substance use disor­der; premenstrual dysphoric disorder; and seasonal affective disorder. Treatments for these subtypes for which there is evi­dence, or a clinical rationale, are given in the Table.

‘Situational depression’
In recent decades, the phenomenon of nonsyndromal depres­sion after a life stress has undergone many name changes but little conceptional revision: “situational,” “reactive,” and “neurotic” labels for depression that were used before DSM-III became “adjustment disorders” in DSM-IV-TR and then “stress response syndromes” in DSM-5. These names all connote presentations of depressed mood after an environmental stressor, with­out either the full constellation of symptoms that define major depression or the chronicity of dysthymic disorder.

Paucity of guidance. There has been little research to identify vulnerability variables for adjustment disorders in the aftermath of particular stressors. Similarly, extensive data are lacking on 1) the likely progression of such disorders to a syndromal form of depression or 2) protective factors against developing clinically significant depres­sion after a life stress. The extent to which adjustment disorders lie on a continuum with major mood disorders is not well-established, although subthreshold levels of depression can predispose to major depres­sion or suicidal behaviors.¹

Models of behavioral sensitization posit that stressful life events more often precede first or early episodes of depression than sub­sequent recurrences.² At the same time, non-melancholic depressions that are preceded by “situational stresses” tend to recur in similar fashion.³

Medical therapy of value? Psychotherapy without medication—apart from occa­sional sedative−hypnotic drugs as needed for insomnia, anxiety, or distress—is con­sidered the standard of care for treating an adjustment disorder. No drug has demon­strated superiority to placebo for alleviating symptoms of an adjustment disorder, but some clinicians nonetheless sometimes feel compelled to “up-code” the diagnosis of an adjustment disorder to the status of a major affective disorder, even when syndromal cri­teria for major depressive disorder (MDD) or dysthymia are absent.

Treatment-resistant depression
Disease staging models for depression and other psychiatric disorders^a make note that, elsewhere in medicine, distinct clinical entities often are identified based on their responsivity to treatment (eg, classifying infections as antibiotic-sensitive or -resis­tant). Within the study and management of mood disorders, “treatment resistance” sometimes is a catch-all description of situ­ations in which past treatment 1) yielded no improvement or partial improvement or 2) was marked by intolerance. Poor out­comes due to past medication intolerance or an aborted trial often are commingled with cases of true lack of improvement after an adequate treatment trial.

^aSee “Staging psychiatric disorders: A clinico-biologic model,” Current Psychiatry, May 2013, at CurrentPsychiatry.com.

It is useful, therefore, to define terminology precisely when describing “treatment-resistant depression” and “treatment-refractory depres­sion.” True past nonresponse to appropriate treatment often carries prognostic importance and bears on future treatment decisions.

Few interventions are FDA approved for treatment-resistant depression (Table).

Neuromodulation techniques are attract­ing interest in this area, although repetitive transcranial magnetic stimulation appears inferior to electroconvulsive therapy (ECT) for this indication.⁴

Melancholic depression
Melancholia involves the cardinal symptoms of anhedonia and lack of mood reactivity, alongside such features as distinct quality of mood, diurnal variation, excessive guilt, and severe weight loss. It most closely approxi­mates pre-DSM-III “endogenous depres­sion” and can involve 1) greater genetic loading⁵ and 2) structural and functional abnormalities in frontostriatal pathways.^6,7

Melancholic features do not necessarily recur across successive episodes⁸ but carry an increased risk of psychosis⁹ and high-lethality suicidal behavior.¹⁰ Melancholia implies necessity for pharmacotherapy or ECT rather than psychosocial treatment alone; some researchers have suggested that tricyclic antidepressants (TCAs) might yield better results than selective serotonin reup­take inhibitors (SSRIs).¹¹

Agitated depression
The Research Diagnostic Criteria (a forerun­ner in the 1970s to DSM-III) described agi­tated depression, but the disorder was not included in any DSM editions—although it is a “clinical modification” for MDD in the 10th revision of the International Statistical Classification of Diseases and Related Health Problems.

Agitated depression refers to a major depressive episode involving motor or psy­chic agitation, intense inner tension, and rac­ing or “crowded” thoughts. Some experts believe that it represents a variant of psy­chotic depression or a bipolar mixed state, but the construct does not specify that criteria for a full manic or hypomanic episode exist.

Recovery from agitated depression tends to be slower than in non-agitated depression. Treatment usually entails an antidepressant plus an antipsychotic, although some believe that antidepressants can exacerbate, not alle­viate, symptoms and, instead, favor antipsy­chotics, mood stabilizers, or ECT.¹²

Anxious depression
Anxiety symptoms or syndromes occur in at least one-half of outpatients who have major depression, and might account for a substan­tial percentage of nonresponse to first-line antidepressant therapies.¹³ The construct of a mixed anxiety−depressive disorder is, in fact, well-represented in the literature, particu­larly in primary care medicine, but its poor inter-rater reliability in DSM-5 field trials led to its exclusion there as a formal diagnosis.¹⁴

Serotonergic antidepressants remain the mainstay of treatment for depression with anxiety, although (contrary to popular percep­tion) bupropion exerts an anxiolytic effect that is comparable to the effect of SSRIs.¹⁵ Notably, high somatic anxiety during depression might predict a poor outcome from ECT.¹⁶

Atypical depression
Often closely linked with early onset and chronicity, the construct of atypical depres­sion has been defined in the literature by the symptom constellation of:

• mood reactiveness to environmental circumstances (unlike melancholia)
• heightened interpersonal sensitivity
• hypersomnia
• hyperphagia
• profound fatigue or a sense of physical heaviness.

Some authorities regard atypical fea­tures as being especially common in bipolar depression, or in depression among people who have borderline personality disorder.

Particular interest in this construct grew from studies that suggested that atypical depression is more responsive to a monoamine oxidase inhibitor (MAOI) than to a TCA, but also that SSRIs are not clearly superior to MAOIs.¹⁷ Response to ECT might also be bet­ter in atypical than in typical depression.¹⁸

Depression with a substance use disorder
Although not a distinct diagnostic entity, depression with a coexisting substance use disorder poses special challenges with regard to the source of symptom emergence (that is, when does depression lead to drug or alcohol use to “self medicate,” and when does drug use cause depression?) and treat­ment. Debate continues about whether 1) medicines that treat depression are effec­tive and worthwhile in the setting of active substance use or 2) aggressive treatment of substance misuse is a prerequisite for sub­sequent pharmacotherapy for depression that is “uncontaminated” by the psychotoxic effects of concurrent substances of abuse.

Meta-analysis of controlled trials of antidepressants for patients who have MDD or a dysthymic disorder plus a comorbid alcohol use disorder found that antidepressants were, overall, superior to placebo unless a patient is actively drink­ing.¹⁹ Of the various classes of antidepres­sants, TCAs and nefazodone were found to be superior to placebo but, surprisingly, SSRIs were not. Another meta-analysis of adjunctive antidepressant outcomes for opiate-dependent, depressed patients who are receiving methadone maintenance therapy found no difference between anti­depressants and placebo in their effect on depression symptom outcomes.²⁰

Premenstrual dysphoric disorder
A new category in DSM-5, premenstrual dysphoric disorder (PMDD) represents a variant of premenstrual syndrome that arises during the luteal phase and ends with menstruation. Symptoms include several of those identified with MDD (without duration criteria), as well as mood swings, panic attacks, and physi­cal complaints.

SSRIs—but not bupropion²¹ or TCAs²²— and, sometimes, low-estrogen oral contra­ceptives are mainstays of treatment; so is cognitive-behavioral therapy, as well as life­style modifications (eg, exercise and changes to diet). Phototherapy has not shown robust efficacy for PMDD.²³

Secondary depression
In DSM-5, depressive episodes that arise secondary to a general medical condition (eg, hypothyroidism and other endocrinopa­thies, cerebrovascular accidents, malignan­cies) or iatrogenically from medications (eg, corticosteroids, some anticonvulsants, interinter­feron) are viewed as distinct from MDD in regard to risk of recurrence, genetic under­pinnings, and possible neurodegenerative pathophysiology.^b Unlike MDD, patient-specific risk factors are poorly defined for anticipating that a secondary depression is more or less likely to develop in the context of an exogenous substance or medical illness.

^bFor further discussion, see “Is a medical illness causing your patient’s depression? Current Psychiatry, August 2009, at CurrentPsychiatry.com.

Treating secondary depression involves addressing the underlying condition and might include antidepressant medication.

Seasonal affective disorder
DSM-5 identifies “with seasonal pattern” as a specifier for recurrent major depression. Phototherapy remains a standard treatment, although a Cochrane Review identified comparable outcomes with fluoxetine, but inconclusive data for other, newer antide­pressants.²⁴ Small open trials have suggested that MAOIs and TCAs can be efficacious.

Note: Phototherapy lacks demonstrated efficacy in non-seasonal forms of depression.²⁵

What does the future hold for classifying depressive disorders?
Recent initiatives have attempted to classify depression less by traditional clinical signs and more by focusing on possible underly­ing neurobiological substrates.^c In the future, subtyping of mood disorders might focus on such constructs as:

• positive and negative valence systems and attentional domains
• treatment-responsivity relative to genotypic variants (for example, the sero­tonin transporter gene locus [SLC6A4] or prediction of L-methylfolate-responsive depression based on the genotype of the methylenetetrahydrofolate reductase [MTHFR] polymorphism)
• disrupted neural plasticity in brain cir­cuits believed to regulate emotion.

^cAn example is the Research Domain Criteria [RDoC],www. nimh.nih.gov/research-priorities/rdoc/index.shtml.

Until robust biomarkers for depression are identified and validated, however, such advances in nosology remain experi­mental and speculative.


BOTTOM LINE
Depressive disorders comprise a range of conditions that can be viewed along many dimensions, including “situational,” treatment-resistant, melancholic, agitated, anxious, and atypical depression; depression occurring with a substance use disorder; premenstrual dysphoric disorder; and seasonal affective disorder, among other classifications. Clinical characteristics vary across subtypes—as do corresponding preferred treatments, which should be tailored to the needs of your patients.


Editor’s note: The first part of Dr. Goldberg’s review of depression subtypes—focusing on major and minor depression, chronicity, polar­ity, severity, and psychosis—appeared in the April 2014 issue.


Related Resources
• Kosinski EC, Rothschild AJ. Monoamine oxidase inhibitors: Forgotten treatment for depression. Current Psychiatry. 2012;11(12):20-26.
• Rodgers S, Grosse Holtforth M, Müller M, et al. Symptom-based subtypes of depression and their psychosocial cor­relates: a person-centered approach focusing on the influ­ence of sex. J Affect Disord. 2014;156:92-103.

Drug Brand Names
Aripiprazole • Abilify               Mirtazapine • Remeron
Bupropion • Wellbutrin            Nefazodone • Serzone
Fluoxetine • Prozac                 Olanzapine/fluoxetine • Symbyax
Ketamine • Ketalar                 Pramipexole • Mirapex
L-Methylfolate • Deplin           Quetiapine • Seroquel
Lamotrigine • Lamictal            Riluzole • Rilutek
Lithium • Eskalith, Lithobid      Vortioxetine • Brintellix
Methadone • Dolophine

Disclosure
Dr. Goldberg has been a consultant to Avanir Pharmaceuticals and Merck; has served on the speakers’ bureau for AstraZeneca, Merck, Novartis, Sunovion Pharmaceuticals, Takeda-Lundbeck; and has received royalties from American Psychiatric Publishing and honoraria from Medscape and WebMD.

Depression—sad, empty, or irritable mood accompanied by somatic or cognitive changes—is not a homoge­neous condition. Recognizing subtypes of depressive illness can guide treatment and relieve your patient’s suf­fering. In this 2-part article [April and May 2014 issues], I summarize information about clinically distinct subtypes of depression, as they are recognized within diagnostic systems or as descriptors of treatment outcomes for particular sub­groups of patients. My focus is on practical considerations for assessing and managing depression. Because many forms of the disorder respond inadequately to initial antidepressant treatment, optimal “next-step” pharmacotherapy, after nonre­sponse or partial response, often hinges on clinical subtyping.

The second part of this article examines “situational,” treat­ment-resistant, melancholic, agitated, anxious, and atypical depression; depression occurring with a substance use disor­der; premenstrual dysphoric disorder; and seasonal affective disorder. Treatments for these subtypes for which there is evi­dence, or a clinical rationale, are given in the Table.

‘Situational depression’
In recent decades, the phenomenon of nonsyndromal depres­sion after a life stress has undergone many name changes but little conceptional revision: “situational,” “reactive,” and “neurotic” labels for depression that were used before DSM-III became “adjustment disorders” in DSM-IV-TR and then “stress response syndromes” in DSM-5. These names all connote presentations of depressed mood after an environmental stressor, with­out either the full constellation of symptoms that define major depression or the chronicity of dysthymic disorder.

Paucity of guidance. There has been little research to identify vulnerability variables for adjustment disorders in the aftermath of particular stressors. Similarly, extensive data are lacking on 1) the likely progression of such disorders to a syndromal form of depression or 2) protective factors against developing clinically significant depres­sion after a life stress. The extent to which adjustment disorders lie on a continuum with major mood disorders is not well-established, although subthreshold levels of depression can predispose to major depres­sion or suicidal behaviors.¹

Models of behavioral sensitization posit that stressful life events more often precede first or early episodes of depression than sub­sequent recurrences.² At the same time, non-melancholic depressions that are preceded by “situational stresses” tend to recur in similar fashion.³

Medical therapy of value? Psychotherapy without medication—apart from occa­sional sedative−hypnotic drugs as needed for insomnia, anxiety, or distress—is con­sidered the standard of care for treating an adjustment disorder. No drug has demon­strated superiority to placebo for alleviating symptoms of an adjustment disorder, but some clinicians nonetheless sometimes feel compelled to “up-code” the diagnosis of an adjustment disorder to the status of a major affective disorder, even when syndromal cri­teria for major depressive disorder (MDD) or dysthymia are absent.

Treatment-resistant depression
Disease staging models for depression and other psychiatric disorders^a make note that, elsewhere in medicine, distinct clinical entities often are identified based on their responsivity to treatment (eg, classifying infections as antibiotic-sensitive or -resis­tant). Within the study and management of mood disorders, “treatment resistance” sometimes is a catch-all description of situ­ations in which past treatment 1) yielded no improvement or partial improvement or 2) was marked by intolerance. Poor out­comes due to past medication intolerance or an aborted trial often are commingled with cases of true lack of improvement after an adequate treatment trial.

^aSee “Staging psychiatric disorders: A clinico-biologic model,” Current Psychiatry, May 2013, at CurrentPsychiatry.com.

It is useful, therefore, to define terminology precisely when describing “treatment-resistant depression” and “treatment-refractory depres­sion.” True past nonresponse to appropriate treatment often carries prognostic importance and bears on future treatment decisions.

Few interventions are FDA approved for treatment-resistant depression (Table).

Neuromodulation techniques are attract­ing interest in this area, although repetitive transcranial magnetic stimulation appears inferior to electroconvulsive therapy (ECT) for this indication.⁴

Melancholic depression
Melancholia involves the cardinal symptoms of anhedonia and lack of mood reactivity, alongside such features as distinct quality of mood, diurnal variation, excessive guilt, and severe weight loss. It most closely approxi­mates pre-DSM-III “endogenous depres­sion” and can involve 1) greater genetic loading⁵ and 2) structural and functional abnormalities in frontostriatal pathways.^6,7

Melancholic features do not necessarily recur across successive episodes⁸ but carry an increased risk of psychosis⁹ and high-lethality suicidal behavior.¹⁰ Melancholia implies necessity for pharmacotherapy or ECT rather than psychosocial treatment alone; some researchers have suggested that tricyclic antidepressants (TCAs) might yield better results than selective serotonin reup­take inhibitors (SSRIs).¹¹

Agitated depression
The Research Diagnostic Criteria (a forerun­ner in the 1970s to DSM-III) described agi­tated depression, but the disorder was not included in any DSM editions—although it is a “clinical modification” for MDD in the 10th revision of the International Statistical Classification of Diseases and Related Health Problems.

Agitated depression refers to a major depressive episode involving motor or psy­chic agitation, intense inner tension, and rac­ing or “crowded” thoughts. Some experts believe that it represents a variant of psy­chotic depression or a bipolar mixed state, but the construct does not specify that criteria for a full manic or hypomanic episode exist.

Recovery from agitated depression tends to be slower than in non-agitated depression. Treatment usually entails an antidepressant plus an antipsychotic, although some believe that antidepressants can exacerbate, not alle­viate, symptoms and, instead, favor antipsy­chotics, mood stabilizers, or ECT.¹²

Anxious depression
Anxiety symptoms or syndromes occur in at least one-half of outpatients who have major depression, and might account for a substan­tial percentage of nonresponse to first-line antidepressant therapies.¹³ The construct of a mixed anxiety−depressive disorder is, in fact, well-represented in the literature, particu­larly in primary care medicine, but its poor inter-rater reliability in DSM-5 field trials led to its exclusion there as a formal diagnosis.¹⁴

Serotonergic antidepressants remain the mainstay of treatment for depression with anxiety, although (contrary to popular percep­tion) bupropion exerts an anxiolytic effect that is comparable to the effect of SSRIs.¹⁵ Notably, high somatic anxiety during depression might predict a poor outcome from ECT.¹⁶

Atypical depression
Often closely linked with early onset and chronicity, the construct of atypical depres­sion has been defined in the literature by the symptom constellation of:

• mood reactiveness to environmental circumstances (unlike melancholia)
• heightened interpersonal sensitivity
• hypersomnia
• hyperphagia
• profound fatigue or a sense of physical heaviness.

Some authorities regard atypical fea­tures as being especially common in bipolar depression, or in depression among people who have borderline personality disorder.

Particular interest in this construct grew from studies that suggested that atypical depression is more responsive to a monoamine oxidase inhibitor (MAOI) than to a TCA, but also that SSRIs are not clearly superior to MAOIs.¹⁷ Response to ECT might also be bet­ter in atypical than in typical depression.¹⁸

Depression with a substance use disorder
Although not a distinct diagnostic entity, depression with a coexisting substance use disorder poses special challenges with regard to the source of symptom emergence (that is, when does depression lead to drug or alcohol use to “self medicate,” and when does drug use cause depression?) and treat­ment. Debate continues about whether 1) medicines that treat depression are effec­tive and worthwhile in the setting of active substance use or 2) aggressive treatment of substance misuse is a prerequisite for sub­sequent pharmacotherapy for depression that is “uncontaminated” by the psychotoxic effects of concurrent substances of abuse.

Meta-analysis of controlled trials of antidepressants for patients who have MDD or a dysthymic disorder plus a comorbid alcohol use disorder found that antidepressants were, overall, superior to placebo unless a patient is actively drink­ing.¹⁹ Of the various classes of antidepres­sants, TCAs and nefazodone were found to be superior to placebo but, surprisingly, SSRIs were not. Another meta-analysis of adjunctive antidepressant outcomes for opiate-dependent, depressed patients who are receiving methadone maintenance therapy found no difference between anti­depressants and placebo in their effect on depression symptom outcomes.²⁰

Premenstrual dysphoric disorder
A new category in DSM-5, premenstrual dysphoric disorder (PMDD) represents a variant of premenstrual syndrome that arises during the luteal phase and ends with menstruation. Symptoms include several of those identified with MDD (without duration criteria), as well as mood swings, panic attacks, and physi­cal complaints.

SSRIs—but not bupropion²¹ or TCAs²²— and, sometimes, low-estrogen oral contra­ceptives are mainstays of treatment; so is cognitive-behavioral therapy, as well as life­style modifications (eg, exercise and changes to diet). Phototherapy has not shown robust efficacy for PMDD.²³

Secondary depression
In DSM-5, depressive episodes that arise secondary to a general medical condition (eg, hypothyroidism and other endocrinopa­thies, cerebrovascular accidents, malignan­cies) or iatrogenically from medications (eg, corticosteroids, some anticonvulsants, interinter­feron) are viewed as distinct from MDD in regard to risk of recurrence, genetic under­pinnings, and possible neurodegenerative pathophysiology.^b Unlike MDD, patient-specific risk factors are poorly defined for anticipating that a secondary depression is more or less likely to develop in the context of an exogenous substance or medical illness.

^bFor further discussion, see “Is a medical illness causing your patient’s depression? Current Psychiatry, August 2009, at CurrentPsychiatry.com.

Treating secondary depression involves addressing the underlying condition and might include antidepressant medication.

Seasonal affective disorder
DSM-5 identifies “with seasonal pattern” as a specifier for recurrent major depression. Phototherapy remains a standard treatment, although a Cochrane Review identified comparable outcomes with fluoxetine, but inconclusive data for other, newer antide­pressants.²⁴ Small open trials have suggested that MAOIs and TCAs can be efficacious.

Note: Phototherapy lacks demonstrated efficacy in non-seasonal forms of depression.²⁵

What does the future hold for classifying depressive disorders?
Recent initiatives have attempted to classify depression less by traditional clinical signs and more by focusing on possible underly­ing neurobiological substrates.^c In the future, subtyping of mood disorders might focus on such constructs as:

• positive and negative valence systems and attentional domains
• treatment-responsivity relative to genotypic variants (for example, the sero­tonin transporter gene locus [SLC6A4] or prediction of L-methylfolate-responsive depression based on the genotype of the methylenetetrahydrofolate reductase [MTHFR] polymorphism)
• disrupted neural plasticity in brain cir­cuits believed to regulate emotion.

^cAn example is the Research Domain Criteria [RDoC],www. nimh.nih.gov/research-priorities/rdoc/index.shtml.

Until robust biomarkers for depression are identified and validated, however, such advances in nosology remain experi­mental and speculative.


BOTTOM LINE
Depressive disorders comprise a range of conditions that can be viewed along many dimensions, including “situational,” treatment-resistant, melancholic, agitated, anxious, and atypical depression; depression occurring with a substance use disorder; premenstrual dysphoric disorder; and seasonal affective disorder, among other classifications. Clinical characteristics vary across subtypes—as do corresponding preferred treatments, which should be tailored to the needs of your patients.


Editor’s note: The first part of Dr. Goldberg’s review of depression subtypes—focusing on major and minor depression, chronicity, polar­ity, severity, and psychosis—appeared in the April 2014 issue.


Related Resources
• Kosinski EC, Rothschild AJ. Monoamine oxidase inhibitors: Forgotten treatment for depression. Current Psychiatry. 2012;11(12):20-26.
• Rodgers S, Grosse Holtforth M, Müller M, et al. Symptom-based subtypes of depression and their psychosocial cor­relates: a person-centered approach focusing on the influ­ence of sex. J Affect Disord. 2014;156:92-103.

Drug Brand Names
Aripiprazole • Abilify               Mirtazapine • Remeron
Bupropion • Wellbutrin            Nefazodone • Serzone
Fluoxetine • Prozac                 Olanzapine/fluoxetine • Symbyax
Ketamine • Ketalar                 Pramipexole • Mirapex
L-Methylfolate • Deplin           Quetiapine • Seroquel
Lamotrigine • Lamictal            Riluzole • Rilutek
Lithium • Eskalith, Lithobid      Vortioxetine • Brintellix
Methadone • Dolophine

Disclosure
Dr. Goldberg has been a consultant to Avanir Pharmaceuticals and Merck; has served on the speakers’ bureau for AstraZeneca, Merck, Novartis, Sunovion Pharmaceuticals, Takeda-Lundbeck; and has received royalties from American Psychiatric Publishing and honoraria from Medscape and WebMD.

Depression—sad, empty, or irritable mood accompanied by somatic or cognitive changes—is not a homoge­neous condition. Recognizing subtypes of depressive illness can guide treatment and relieve your patient’s suf­fering. In this 2-part article [April and May 2014 issues], I summarize information about clinically distinct subtypes of depression, as they are recognized within diagnostic systems or as descriptors of treatment outcomes for particular sub­groups of patients. My focus is on practical considerations for assessing and managing depression. Because many forms of the disorder respond inadequately to initial antidepressant treatment, optimal “next-step” pharmacotherapy, after nonre­sponse or partial response, often hinges on clinical subtyping.

The second part of this article examines “situational,” treat­ment-resistant, melancholic, agitated, anxious, and atypical depression; depression occurring with a substance use disor­der; premenstrual dysphoric disorder; and seasonal affective disorder. Treatments for these subtypes for which there is evi­dence, or a clinical rationale, are given in the Table.

‘Situational depression’
In recent decades, the phenomenon of nonsyndromal depres­sion after a life stress has undergone many name changes but little conceptional revision: “situational,” “reactive,” and “neurotic” labels for depression that were used before DSM-III became “adjustment disorders” in DSM-IV-TR and then “stress response syndromes” in DSM-5. These names all connote presentations of depressed mood after an environmental stressor, with­out either the full constellation of symptoms that define major depression or the chronicity of dysthymic disorder.

Paucity of guidance. There has been little research to identify vulnerability variables for adjustment disorders in the aftermath of particular stressors. Similarly, extensive data are lacking on 1) the likely progression of such disorders to a syndromal form of depression or 2) protective factors against developing clinically significant depres­sion after a life stress. The extent to which adjustment disorders lie on a continuum with major mood disorders is not well-established, although subthreshold levels of depression can predispose to major depres­sion or suicidal behaviors.¹

Models of behavioral sensitization posit that stressful life events more often precede first or early episodes of depression than sub­sequent recurrences.² At the same time, non-melancholic depressions that are preceded by “situational stresses” tend to recur in similar fashion.³

Medical therapy of value? Psychotherapy without medication—apart from occa­sional sedative−hypnotic drugs as needed for insomnia, anxiety, or distress—is con­sidered the standard of care for treating an adjustment disorder. No drug has demon­strated superiority to placebo for alleviating symptoms of an adjustment disorder, but some clinicians nonetheless sometimes feel compelled to “up-code” the diagnosis of an adjustment disorder to the status of a major affective disorder, even when syndromal cri­teria for major depressive disorder (MDD) or dysthymia are absent.

Treatment-resistant depression
Disease staging models for depression and other psychiatric disorders^a make note that, elsewhere in medicine, distinct clinical entities often are identified based on their responsivity to treatment (eg, classifying infections as antibiotic-sensitive or -resis­tant). Within the study and management of mood disorders, “treatment resistance” sometimes is a catch-all description of situ­ations in which past treatment 1) yielded no improvement or partial improvement or 2) was marked by intolerance. Poor out­comes due to past medication intolerance or an aborted trial often are commingled with cases of true lack of improvement after an adequate treatment trial.

^aSee “Staging psychiatric disorders: A clinico-biologic model,” Current Psychiatry, May 2013, at CurrentPsychiatry.com.

It is useful, therefore, to define terminology precisely when describing “treatment-resistant depression” and “treatment-refractory depres­sion.” True past nonresponse to appropriate treatment often carries prognostic importance and bears on future treatment decisions.

Few interventions are FDA approved for treatment-resistant depression (Table).

Neuromodulation techniques are attract­ing interest in this area, although repetitive transcranial magnetic stimulation appears inferior to electroconvulsive therapy (ECT) for this indication.⁴

Melancholic depression
Melancholia involves the cardinal symptoms of anhedonia and lack of mood reactivity, alongside such features as distinct quality of mood, diurnal variation, excessive guilt, and severe weight loss. It most closely approxi­mates pre-DSM-III “endogenous depres­sion” and can involve 1) greater genetic loading⁵ and 2) structural and functional abnormalities in frontostriatal pathways.^6,7

Melancholic features do not necessarily recur across successive episodes⁸ but carry an increased risk of psychosis⁹ and high-lethality suicidal behavior.¹⁰ Melancholia implies necessity for pharmacotherapy or ECT rather than psychosocial treatment alone; some researchers have suggested that tricyclic antidepressants (TCAs) might yield better results than selective serotonin reup­take inhibitors (SSRIs).¹¹

Agitated depression
The Research Diagnostic Criteria (a forerun­ner in the 1970s to DSM-III) described agi­tated depression, but the disorder was not included in any DSM editions—although it is a “clinical modification” for MDD in the 10th revision of the International Statistical Classification of Diseases and Related Health Problems.

Agitated depression refers to a major depressive episode involving motor or psy­chic agitation, intense inner tension, and rac­ing or “crowded” thoughts. Some experts believe that it represents a variant of psy­chotic depression or a bipolar mixed state, but the construct does not specify that criteria for a full manic or hypomanic episode exist.

Recovery from agitated depression tends to be slower than in non-agitated depression. Treatment usually entails an antidepressant plus an antipsychotic, although some believe that antidepressants can exacerbate, not alle­viate, symptoms and, instead, favor antipsy­chotics, mood stabilizers, or ECT.¹²

Anxious depression
Anxiety symptoms or syndromes occur in at least one-half of outpatients who have major depression, and might account for a substan­tial percentage of nonresponse to first-line antidepressant therapies.¹³ The construct of a mixed anxiety−depressive disorder is, in fact, well-represented in the literature, particu­larly in primary care medicine, but its poor inter-rater reliability in DSM-5 field trials led to its exclusion there as a formal diagnosis.¹⁴

Serotonergic antidepressants remain the mainstay of treatment for depression with anxiety, although (contrary to popular percep­tion) bupropion exerts an anxiolytic effect that is comparable to the effect of SSRIs.¹⁵ Notably, high somatic anxiety during depression might predict a poor outcome from ECT.¹⁶

Atypical depression
Often closely linked with early onset and chronicity, the construct of atypical depres­sion has been defined in the literature by the symptom constellation of:

• mood reactiveness to environmental circumstances (unlike melancholia)
• heightened interpersonal sensitivity
• hypersomnia
• hyperphagia
• profound fatigue or a sense of physical heaviness.

Some authorities regard atypical fea­tures as being especially common in bipolar depression, or in depression among people who have borderline personality disorder.

Particular interest in this construct grew from studies that suggested that atypical depression is more responsive to a monoamine oxidase inhibitor (MAOI) than to a TCA, but also that SSRIs are not clearly superior to MAOIs.¹⁷ Response to ECT might also be bet­ter in atypical than in typical depression.¹⁸

Depression with a substance use disorder
Although not a distinct diagnostic entity, depression with a coexisting substance use disorder poses special challenges with regard to the source of symptom emergence (that is, when does depression lead to drug or alcohol use to “self medicate,” and when does drug use cause depression?) and treat­ment. Debate continues about whether 1) medicines that treat depression are effec­tive and worthwhile in the setting of active substance use or 2) aggressive treatment of substance misuse is a prerequisite for sub­sequent pharmacotherapy for depression that is “uncontaminated” by the psychotoxic effects of concurrent substances of abuse.

Meta-analysis of controlled trials of antidepressants for patients who have MDD or a dysthymic disorder plus a comorbid alcohol use disorder found that antidepressants were, overall, superior to placebo unless a patient is actively drink­ing.¹⁹ Of the various classes of antidepres­sants, TCAs and nefazodone were found to be superior to placebo but, surprisingly, SSRIs were not. Another meta-analysis of adjunctive antidepressant outcomes for opiate-dependent, depressed patients who are receiving methadone maintenance therapy found no difference between anti­depressants and placebo in their effect on depression symptom outcomes.²⁰

Premenstrual dysphoric disorder
A new category in DSM-5, premenstrual dysphoric disorder (PMDD) represents a variant of premenstrual syndrome that arises during the luteal phase and ends with menstruation. Symptoms include several of those identified with MDD (without duration criteria), as well as mood swings, panic attacks, and physi­cal complaints.

SSRIs—but not bupropion²¹ or TCAs²²— and, sometimes, low-estrogen oral contra­ceptives are mainstays of treatment; so is cognitive-behavioral therapy, as well as life­style modifications (eg, exercise and changes to diet). Phototherapy has not shown robust efficacy for PMDD.²³

Secondary depression
In DSM-5, depressive episodes that arise secondary to a general medical condition (eg, hypothyroidism and other endocrinopa­thies, cerebrovascular accidents, malignan­cies) or iatrogenically from medications (eg, corticosteroids, some anticonvulsants, interinter­feron) are viewed as distinct from MDD in regard to risk of recurrence, genetic under­pinnings, and possible neurodegenerative pathophysiology.^b Unlike MDD, patient-specific risk factors are poorly defined for anticipating that a secondary depression is more or less likely to develop in the context of an exogenous substance or medical illness.

^bFor further discussion, see “Is a medical illness causing your patient’s depression? Current Psychiatry, August 2009, at CurrentPsychiatry.com.

Treating secondary depression involves addressing the underlying condition and might include antidepressant medication.

Seasonal affective disorder
DSM-5 identifies “with seasonal pattern” as a specifier for recurrent major depression. Phototherapy remains a standard treatment, although a Cochrane Review identified comparable outcomes with fluoxetine, but inconclusive data for other, newer antide­pressants.²⁴ Small open trials have suggested that MAOIs and TCAs can be efficacious.

Note: Phototherapy lacks demonstrated efficacy in non-seasonal forms of depression.²⁵

What does the future hold for classifying depressive disorders?
Recent initiatives have attempted to classify depression less by traditional clinical signs and more by focusing on possible underly­ing neurobiological substrates.^c In the future, subtyping of mood disorders might focus on such constructs as:

• positive and negative valence systems and attentional domains
• treatment-responsivity relative to genotypic variants (for example, the sero­tonin transporter gene locus [SLC6A4] or prediction of L-methylfolate-responsive depression based on the genotype of the methylenetetrahydrofolate reductase [MTHFR] polymorphism)
• disrupted neural plasticity in brain cir­cuits believed to regulate emotion.

^cAn example is the Research Domain Criteria [RDoC],www. nimh.nih.gov/research-priorities/rdoc/index.shtml.

Until robust biomarkers for depression are identified and validated, however, such advances in nosology remain experi­mental and speculative.


BOTTOM LINE
Depressive disorders comprise a range of conditions that can be viewed along many dimensions, including “situational,” treatment-resistant, melancholic, agitated, anxious, and atypical depression; depression occurring with a substance use disorder; premenstrual dysphoric disorder; and seasonal affective disorder, among other classifications. Clinical characteristics vary across subtypes—as do corresponding preferred treatments, which should be tailored to the needs of your patients.


Editor’s note: The first part of Dr. Goldberg’s review of depression subtypes—focusing on major and minor depression, chronicity, polar­ity, severity, and psychosis—appeared in the April 2014 issue.


Related Resources
• Kosinski EC, Rothschild AJ. Monoamine oxidase inhibitors: Forgotten treatment for depression. Current Psychiatry. 2012;11(12):20-26.
• Rodgers S, Grosse Holtforth M, Müller M, et al. Symptom-based subtypes of depression and their psychosocial cor­relates: a person-centered approach focusing on the influ­ence of sex. J Affect Disord. 2014;156:92-103.

Drug Brand Names
Aripiprazole • Abilify               Mirtazapine • Remeron
Bupropion • Wellbutrin            Nefazodone • Serzone
Fluoxetine • Prozac                 Olanzapine/fluoxetine • Symbyax
Ketamine • Ketalar                 Pramipexole • Mirapex
L-Methylfolate • Deplin           Quetiapine • Seroquel
Lamotrigine • Lamictal            Riluzole • Rilutek
Lithium • Eskalith, Lithobid      Vortioxetine • Brintellix
Methadone • Dolophine

Disclosure
Dr. Goldberg has been a consultant to Avanir Pharmaceuticals and Merck; has served on the speakers’ bureau for AstraZeneca, Merck, Novartis, Sunovion Pharmaceuticals, Takeda-Lundbeck; and has received royalties from American Psychiatric Publishing and honoraria from Medscape and WebMD.