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A Case of Possible Iatrogenic Ketamine-Induced Mania in a Patient Being Treated for Postoperative Pain
Author's Accepted Manuscript
A Case of Possible Iatrogenic Ketamine-Induced Mania in a Patient Being Treated for PostOperative Pain Stephanie Nichols, Maya Bulman, Annya Tisher, John Campbell
PII: DOI: Reference:
S0033-3182(16)30058-5 http://dx.doi.org/10.1016/j.psym.2016.06.003 PSYM653
To appear in:
Psychosomatics
Cite this article as: Stephanie Nichols, Maya Bulman, Annya Tisher, John Campbell, A Case of Possible Iatrogenic Ketamine-Induced Mania in a Patient Being Treated for Post-Operative Pain, Psychosomatics, http://dx.doi.org/10.1016/j. psym.2016.06.003 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Title: A Case of Possible Iatrogenic Ketamine-Induced Mania in a Patient Being Treated for Post-Operative Pain Nichols, Stephanie; Husson University School of Pharmacy, Pharmacy Practice; Maine Medical Center, Psychiatry; Tufts University School of Medicine, Psychiatry Bulman, Maya; Maine Medical Center, Psychiatry; Tufts University School of Medicine, Psychiatry Tisher, Annya; Yale University School of Medicine, Neurology; Yale-New Haven Hospital, Neurology Campbell, John; Maine Medical Center, Psychiatry; Tufts University School of Medicine, Psychiatry
Keywords: ketamine, mania, acute pain, Opioid Use Disorder
Abstract: Ketamine is an N-methyl-D-aspartate (NMDA) antagonist that has become increasingly recognized and utilized in the treatment of post-operative pain as a way to reduce opioid use. Overall ketamine is generally well tolerated, however it is associated with transient hypertension and neurologic “emergence phenomena” manifesting as dream-like states, irrational behavior, and delirium. From a psychiatric perspective, ketamine is known to cause mania in animal models, but evidence in humans is lacking. This report adds a fourth case of possible ketamine-induced mania to the literature, however this is the first case report of mania in a patient with no previously documented family or personal history of Bipolar Disorder. Decreased need for sleep occurred within hours of the initiation of the ketamine infusion and the symptoms of mania progressed throughout the next 3 days culminating on day 4 of ketamine therapy in a full manic episode. Well-known, post-anesthetic “emergence phenomena” after ketamine use differs from our case in that patients are generally somnolent, whereas our patient developed a manic state which took weeks to resolve with olanzapine and lorazepam treatment. This patient was off treatment and symptom free for more than a year before developing a second manic episode and subsequently being diagnosed with Bipolar Disorder. As ketamine is being increasingly used in psychiatric and non psychiatric populations, all providers should be aware of the possibility of an affective switch with the use of ketamine. It is unclear if ketamine can induce mania in susceptible individuals, though this case suggests that it may.
Body: Ketamine is a N-methyl-D-aspartate (NMDA) antagonist that was approved by the FDA in 1970 as an anesthetic agent and has since been studied for use in pain1,2 and treatment refractory status epilepticus3. It has also gained interest as a possible neurochemical model for Schizophrenia4, delusions5, and mania6. Finally, ketamine has been identified as having antidepressant properties in humans7. This report adds to previous case8, 9 reports of adverse psychiatric reactions to ketamine and describes a case of ketamine-induced mania in a patient with no previously documented family or personal history of Bipolar Disorder. Additionally, the literature will be reviewed and ketamine’s pharmacology will be discussed. The patient is a 27-year-old, 86.6kg, African American man with multiple Substance Use Disorders (SUD), but no past medical history and no prescribed medications, who presented to the hospital complaining of severe buttock pain and left leg weakness. He reported using intravenous (IV) heroin on the previous evening and awoke unable to move his left leg. His medical physician initially described his affect as “reserved”. He was diagnosed with rhabdomyolysis and acute kidney injury (AKI). He was hospitalized and underwent surgical release for a compartment syndrome involving the left leg. Psychiatry was consulted on hospital day 3 (HD3) for evaluation of his SUD. He began using drugs at the age of 14, including alcohol, opioids, cannabis, and cocaine. He had one previous inpatient psychiatric hospitalization one year prior for depression and suicidal ideation in the context of active substance use. At that time, he underwent a psychiatric assessment and was diagnosed with an Opioid-Induced Depressive Disorder as well as Opioid, Cannabis, and Cocaine Use Disorders. He reported a family history significant for SUD, depression, and anxiety. Importantly, there was no reported personal or family history of Bipolar Disorder. He was not in psychiatric treatment at the time of the current admission and was taking no medications. During the initial psychiatric interview on HD3, no signs of overt opioid withdrawal were evident. On HD3 he had a surgical decompression and fasciiotomy and was initiated on IV ampicillin/sulbactam therapy. In the days following surgery, the patient tearfully continued to report ongoing and severe “10/10” leg pain despite the use of acetaminophen IV 3000mg/day, gabapentin 400mg/day (dosed for AKI), hydromorphone Patient Controlled Analgesia (PCA) 0.4mg IV every 10 minutes, up to 6mg in 4 hours (average of 30mg per 24h received, which is equivalent to 600mg of morphine), and a single dose of fentanyl 100mcg IV (equivalent to 30mg of morphine). Therefore, on HD9, a ketamine 0.2mg/kg/hr IV infusion was added to the current opioid regimen. The following day, he reported improvement in his pain, and he was noted by a psychiatry consultant to be more energetic. At that time, he expressed a motivation for sobriety and planned “a new direction” in life, including reuniting with his children. He reported a diminished need for sleep, achieving only 2.5 hours that night. On HD12, he was noted to be speaking in a southern accent and “roaring like a lion.” He felt that he was “using more and more of my brain cells”, discussed a plan to donate money to the hospital and stated “I should have been a male model”. Additionally, the patient was hypersexual and disinhibited, as he propositioned a nurse and
was asking about his ability to maintain an erection. Due to these symptoms, he was treated first with quetiapine 200mg with minimal benefit and ultimately required olanzapine 10mg PO which provided moderate benefit and some limited ability to sleep. Given his manic symptoms, ketamine was discontinued on HD12 and a delirium workup was initiated. Complete Metabolic Profile (CMP) was notable only for a resolving AKI and Complete Blood Count (CBC) was notable for a post-operative anemia (hemoglobin 9.7g/dL) and leukocytosis (16.6 x103/uL). A urinalysis was negative for bacteria and glucose. Thyroid testing revealed a slightly elevated Thyroid Stimulating Hormone (TSH) at 9.3mIU/L, however the free T4 was normal at 1.25ng/dL. Secondary to concerns for prolonged QT, an EKG was obtained and revealed J-point elevations. Cardiac enzymes were positive in the setting of an acute rhabdomyolysis, though acute MI was ruled out. A physical exam revealed no focal neurological deficits. At the time of ketamine discontinuation on HD12, he had received 19mg/kg cumulatively over the previous 4 days. Ketamine was continued longer than is typical in an attempt to reduce post-operative opioid requirements. He required up to 20mg of olanzapine and 4mg of lorazepam per day to stabilize his mood and behavior. By HD17, the patient’s inability to sleep began to resolve and he was noted to behave more appropriately. He was weaned off of olanzapine and lorazepam by HD30, and remained euthymic with no further evidence of mood lability. He had no further signs or symptoms of mania until approximately two years after discharge, when he presented to the Emergency Department stating that he is “an enlightened one” and that he had “met God”. His girlfriend reported that he had “barely slept” over the three weeks prior and she noted increased goal directed activity. He was referred to a psychiatric hospital, where he was treated for an acute manic episode and diagnosed with Bipolar Disorder. He was stabilized on quetiapine 850mg/day and lithium 1500mg/day with a lithium level of 0.7mEq/L. He is currently euthymic and tolerating both medications well. Ketamine pharmacology includes: agonist-dependent antagonism of NMDA receptors, weak mu opiate agonism, indirect D2 agonism5, potentiation of glutamate at alpha-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA) receptors and inhibition of muscarinic receptors.10 Doses of ketamine for depression are generally much lower than that used for pain and anesthesia. For example, depression is best treated with 0.5mg/kg as a single infusion7, while post-operative pain infusions are generally dosed with 0.2-1.2mg/kg/hr for up to five days, although 24 – 48 hours is more typical11. FDA approved doses of ketamine for induction of anesthesia range from 1 – 4.5mg/kg as a single high dose intravenous bolus followed by an optional infusion of 0.1 – 0.5mg/min (0.07 – 0.35mg/kg/hr in our patient). Our patient received no bolus and an infusion dose of 0.2mg/kg/hr for 95 hours, which is considered sub-anesthetic dosing, but is much higher than doses used for treatment of depression and moderately longer duration than is typical for pain. Ketamine’s psychomimetic properties in humans have been reported. Post anesthetic “emergence phenomena” may be seen at doses of 2mg/kg and have been described12 as “dream-like states, vivid imagery, hallucinations, and emergence delirium” and can be accompanied by “confusion, excitement, and irrational behavior.” These phenomena generally resolve within a few hours, though can take up to 24 hours. “Emergence phenomena” differ from our case in that patients are generally somnolent and in
a “state resembling cataplexy”, whereas our patient had increased goal directed activity and a reduced need for sleep, which took weeks to resolve. A literature search in PubMed using the terms “ketamine induced mania” was performed. Three cases of ketamine-induced mania were identified. One case8 describes a woman receiving 10-20mg/hr of ketamine (~0.1-0.4mg/kg) for pain who developed emotional lability and irritability within one day, on day 7. Similar to our case, she exhibited euphoria, pressured speech, flight of ideas, and tangentiality. Unlike our case, this patient had a history of possible post-operative hypomanic symptoms. Her infusion was terminated on day 11 and by day 20 her manic syndrome was resolving but hypomania persisted post discharge. The details of this case have been scrutinized and criticized.12, 13 The second case9 describes a patient with known Bipolar Disorder, who developed mania after a single ketamine infusion of 0.5mg/kg. Within 24 hours of treatment, she developed increased energy, hypersexuality, and impulsivity. She required psychiatric hospitalization for mood stabilization. Our case differs from this case because our patient had no history of Bipolar Disorder. The third case14 reported a patient with no history of Bipolar Disorder, who inhaled 5-15g/week of ketamine for 12 months and developed symptoms of mania that persisted for months after cessation of use. The dose and duration of ketamine used in our case was much lower than that used in this recreational ketamine case. Alternative causes of secondary mania should be considered, such as the emergence of complex partial seizures, hyperthyroidism, Cushing’s syndrome, and/or other implicated medications (ex. stimulants, corticosteroids, macrolides, quinolones, and metoclopramide). These were ruled out in our patient as his free T4 was within normal limits, his physical exam was negative for focal neurological deficits, and he was not given any medications that have been implicated in mania other than ketamine. Other factors could have contributed to the emergence of mania in this patient. For example, fentanyl has been reported15 to cause mania at doses of 15,000mcg, but our patient only received 100mcg, making this unlikely to be the cause. Moreover, our patient’s symptoms were unlikely to be due to opioid withdrawal as he remained on high doses of opioids throughout his hospitalization and his opioid dosing was increased, rather than reduced, when ketamine was started. It is possible that perioperative stress and uncontrolled pain could have been a contributing factor in development of mania, along with the ketamine infusion. Interestingly, ketamine is now being studied16 and employed in the treatment of Bipolar Depression. Researchers have evaluated12 “treatment emergent manic like symptoms” in patients with known Bipolar Disorder receiving ketamine, using the Young Mania Rating Scale. Transient mood elevation was noted in a minority of patients, lasting minutes to hours, and therefore contrasts with our patient as his manic symptoms took weeks to resolve. Although the duration and magnitude of these manic symptoms differ, mood elevation was noted after ketamine use in several patients and therefore lends credence to ketamine’s potential to induce mania. In summary, ketamine is known to cause symptoms of mania in animal models6, but definitive evidence in humans in lacking. This report adds a fourth case of possible ketamine induced mania to the literature, however this is the first case report of mania in a patient with no past history of manic or hypomanic symptoms. As ketamine is being increasingly used in psychiatric and non-psychiatric
populations, all providers should be aware of the possibility of an affective switch with the use of ketamine, either as an adverse medication effect, or as an unmasking of an underlying Bipolar Disorder. It is unclear if ketamine can induce mania in susceptible individuals, though this case suggests that it may.
References: 1. Laskowski K, Strilin A, McKay WP, Hyun JL. A Systemic Review of Intravenous Ketamine for PostOperative Analgesia. Can J Anesth. 2011;58:911-23. 2. Fine PG. Low-Dose Ketamine in the Management of Opioid Nonresponsive Terminal Cancer Pain. J Pain Symptom Manage. 1999;17:296-300. 3. Fang Y, Wang X. Ketamine for the treatment of refractory status epilepticus. Seizure. 2015 (Aug);30:14-20. doi: 10.1016/j.seizure.2015.05.010. Epub 2015 May 19. 4. Riedel WJ. The Ketamine Model of Positive, Negative, and Cognitive Symptoms in Schizophrenia: Facts and Frictions. J Psychopharmacol. 2007;21(3):235-6. 5. Corlett PR, Honey GD, Fletcher PC. From Prediction Error to Psychosis: Ketamine as a Pharmacological Model of Delusions. J Psychopharmacol. 2007;21(3):238. 6. Gazal M, Valente MR, Acosta BA, et al. Neuroprotective and Antioxidant Effects of Curcumin in a Ketamine-Induced Model of Mania in Rats. Eur J Pharmacol. 2014;724:132-9. 7. Mathew SJ, Shah A, Lapidus K et al. Ketamine for Treatment-Resistant Unipolar Depression: Current Evidence. CNS Drugs. 2012;26(3):189-204. 8. Ricke AK, Snook RJ, Anand A. Induction of Prolonged Mania During Ketamine Therapy for Reflex Sympathetic Dystrophy. Biol Psychiatry. 2011;70:e13-e14. 9. McInnes LA, James-Meyers MB, Turner MS. Possible affective switch associated with intravenous ketamine treatment in a patient with bipolar I disorder. Biol Psychiatry. 2015 Jul 7. pii: S0006-3223(15)00572-7. doi: 10.1016/j.biopsych.2015.07.003. [Epub ahead of print] 10. Murrough JW. Ketamine as a Novel Antidepressant: From Synapse to Behavior. Clin Pharmacol Ther. 2012;91(2):303-9. 11. Wang L, Johnston B, Kaushal A, Cheng D, Zhu F, Martin J. Ketamine added to morphine or hydromorphone patient-controlled analgesia for acute postoperative pain in adults: a systemic review and meta-analysis of randomized trials. Can J Anesth 2016; 63:311–325.
12. Niciu MJ, Luckenbaugh DA, Ionescu DF, et al. Subanesthetic Dose Ketamine Does Not Induce an Affective Switch in Three Independent Samples of Treatment-Resistant Major Depression. Biol Psychiatry. 2013;74:e23-e24. 13. Altinay M, Anand A. Reply to: Subanesthetic Dose Ketamine Does Not Induce an Affective Switch in Three Independent Samples of Treatment-Resistant Major Depression. Biol Psychiatry. 2013;74:e25. 14. Lu Y, Lin C, Lane H. Mania following ketamine abuse. Neuropsychiatric Disease and Treatment. 2016;12:237-239. 15. Medjugorac H, Horvat N. P.2.g.007 Fentanyl induced organic mania. European Neuropsychopharmacology 2011;21(s3):S444. 16. McCloud TL, Caddy C, Jochim J, Rendell JM, Diamond PR, Shuttleworth C, Brett D, Amit BH, McShane R, Hamadi L, Hawton K, Cipriani A. Ketamine and other glutamate receptor modulators for depression in bipolar disorder in adults. Cochrane Database of Systematic Reviews 2015, Issue 9. Art. No.: CD011611. DOI: 10.1002/14651858.CD011611.pub2.
A Case of Possible Iatrogenic Ketamine-Induced Mania in a Patient Being Treated for PostOperative Pain Stephanie Nichols, Maya Bulman, Annya Tisher, John Campbell
PII: DOI: Reference:
S0033-3182(16)30058-5 http://dx.doi.org/10.1016/j.psym.2016.06.003 PSYM653
To appear in:
Psychosomatics
Cite this article as: Stephanie Nichols, Maya Bulman, Annya Tisher, John Campbell, A Case of Possible Iatrogenic Ketamine-Induced Mania in a Patient Being Treated for Post-Operative Pain, Psychosomatics, http://dx.doi.org/10.1016/j. psym.2016.06.003 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Title: A Case of Possible Iatrogenic Ketamine-Induced Mania in a Patient Being Treated for Post-Operative Pain Nichols, Stephanie; Husson University School of Pharmacy, Pharmacy Practice; Maine Medical Center, Psychiatry; Tufts University School of Medicine, Psychiatry Bulman, Maya; Maine Medical Center, Psychiatry; Tufts University School of Medicine, Psychiatry Tisher, Annya; Yale University School of Medicine, Neurology; Yale-New Haven Hospital, Neurology Campbell, John; Maine Medical Center, Psychiatry; Tufts University School of Medicine, Psychiatry
Keywords: ketamine, mania, acute pain, Opioid Use Disorder
Abstract: Ketamine is an N-methyl-D-aspartate (NMDA) antagonist that has become increasingly recognized and utilized in the treatment of post-operative pain as a way to reduce opioid use. Overall ketamine is generally well tolerated, however it is associated with transient hypertension and neurologic “emergence phenomena” manifesting as dream-like states, irrational behavior, and delirium. From a psychiatric perspective, ketamine is known to cause mania in animal models, but evidence in humans is lacking. This report adds a fourth case of possible ketamine-induced mania to the literature, however this is the first case report of mania in a patient with no previously documented family or personal history of Bipolar Disorder. Decreased need for sleep occurred within hours of the initiation of the ketamine infusion and the symptoms of mania progressed throughout the next 3 days culminating on day 4 of ketamine therapy in a full manic episode. Well-known, post-anesthetic “emergence phenomena” after ketamine use differs from our case in that patients are generally somnolent, whereas our patient developed a manic state which took weeks to resolve with olanzapine and lorazepam treatment. This patient was off treatment and symptom free for more than a year before developing a second manic episode and subsequently being diagnosed with Bipolar Disorder. As ketamine is being increasingly used in psychiatric and non psychiatric populations, all providers should be aware of the possibility of an affective switch with the use of ketamine. It is unclear if ketamine can induce mania in susceptible individuals, though this case suggests that it may.
Body: Ketamine is a N-methyl-D-aspartate (NMDA) antagonist that was approved by the FDA in 1970 as an anesthetic agent and has since been studied for use in pain1,2 and treatment refractory status epilepticus3. It has also gained interest as a possible neurochemical model for Schizophrenia4, delusions5, and mania6. Finally, ketamine has been identified as having antidepressant properties in humans7. This report adds to previous case8, 9 reports of adverse psychiatric reactions to ketamine and describes a case of ketamine-induced mania in a patient with no previously documented family or personal history of Bipolar Disorder. Additionally, the literature will be reviewed and ketamine’s pharmacology will be discussed. The patient is a 27-year-old, 86.6kg, African American man with multiple Substance Use Disorders (SUD), but no past medical history and no prescribed medications, who presented to the hospital complaining of severe buttock pain and left leg weakness. He reported using intravenous (IV) heroin on the previous evening and awoke unable to move his left leg. His medical physician initially described his affect as “reserved”. He was diagnosed with rhabdomyolysis and acute kidney injury (AKI). He was hospitalized and underwent surgical release for a compartment syndrome involving the left leg. Psychiatry was consulted on hospital day 3 (HD3) for evaluation of his SUD. He began using drugs at the age of 14, including alcohol, opioids, cannabis, and cocaine. He had one previous inpatient psychiatric hospitalization one year prior for depression and suicidal ideation in the context of active substance use. At that time, he underwent a psychiatric assessment and was diagnosed with an Opioid-Induced Depressive Disorder as well as Opioid, Cannabis, and Cocaine Use Disorders. He reported a family history significant for SUD, depression, and anxiety. Importantly, there was no reported personal or family history of Bipolar Disorder. He was not in psychiatric treatment at the time of the current admission and was taking no medications. During the initial psychiatric interview on HD3, no signs of overt opioid withdrawal were evident. On HD3 he had a surgical decompression and fasciiotomy and was initiated on IV ampicillin/sulbactam therapy. In the days following surgery, the patient tearfully continued to report ongoing and severe “10/10” leg pain despite the use of acetaminophen IV 3000mg/day, gabapentin 400mg/day (dosed for AKI), hydromorphone Patient Controlled Analgesia (PCA) 0.4mg IV every 10 minutes, up to 6mg in 4 hours (average of 30mg per 24h received, which is equivalent to 600mg of morphine), and a single dose of fentanyl 100mcg IV (equivalent to 30mg of morphine). Therefore, on HD9, a ketamine 0.2mg/kg/hr IV infusion was added to the current opioid regimen. The following day, he reported improvement in his pain, and he was noted by a psychiatry consultant to be more energetic. At that time, he expressed a motivation for sobriety and planned “a new direction” in life, including reuniting with his children. He reported a diminished need for sleep, achieving only 2.5 hours that night. On HD12, he was noted to be speaking in a southern accent and “roaring like a lion.” He felt that he was “using more and more of my brain cells”, discussed a plan to donate money to the hospital and stated “I should have been a male model”. Additionally, the patient was hypersexual and disinhibited, as he propositioned a nurse and
was asking about his ability to maintain an erection. Due to these symptoms, he was treated first with quetiapine 200mg with minimal benefit and ultimately required olanzapine 10mg PO which provided moderate benefit and some limited ability to sleep. Given his manic symptoms, ketamine was discontinued on HD12 and a delirium workup was initiated. Complete Metabolic Profile (CMP) was notable only for a resolving AKI and Complete Blood Count (CBC) was notable for a post-operative anemia (hemoglobin 9.7g/dL) and leukocytosis (16.6 x103/uL). A urinalysis was negative for bacteria and glucose. Thyroid testing revealed a slightly elevated Thyroid Stimulating Hormone (TSH) at 9.3mIU/L, however the free T4 was normal at 1.25ng/dL. Secondary to concerns for prolonged QT, an EKG was obtained and revealed J-point elevations. Cardiac enzymes were positive in the setting of an acute rhabdomyolysis, though acute MI was ruled out. A physical exam revealed no focal neurological deficits. At the time of ketamine discontinuation on HD12, he had received 19mg/kg cumulatively over the previous 4 days. Ketamine was continued longer than is typical in an attempt to reduce post-operative opioid requirements. He required up to 20mg of olanzapine and 4mg of lorazepam per day to stabilize his mood and behavior. By HD17, the patient’s inability to sleep began to resolve and he was noted to behave more appropriately. He was weaned off of olanzapine and lorazepam by HD30, and remained euthymic with no further evidence of mood lability. He had no further signs or symptoms of mania until approximately two years after discharge, when he presented to the Emergency Department stating that he is “an enlightened one” and that he had “met God”. His girlfriend reported that he had “barely slept” over the three weeks prior and she noted increased goal directed activity. He was referred to a psychiatric hospital, where he was treated for an acute manic episode and diagnosed with Bipolar Disorder. He was stabilized on quetiapine 850mg/day and lithium 1500mg/day with a lithium level of 0.7mEq/L. He is currently euthymic and tolerating both medications well. Ketamine pharmacology includes: agonist-dependent antagonism of NMDA receptors, weak mu opiate agonism, indirect D2 agonism5, potentiation of glutamate at alpha-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA) receptors and inhibition of muscarinic receptors.10 Doses of ketamine for depression are generally much lower than that used for pain and anesthesia. For example, depression is best treated with 0.5mg/kg as a single infusion7, while post-operative pain infusions are generally dosed with 0.2-1.2mg/kg/hr for up to five days, although 24 – 48 hours is more typical11. FDA approved doses of ketamine for induction of anesthesia range from 1 – 4.5mg/kg as a single high dose intravenous bolus followed by an optional infusion of 0.1 – 0.5mg/min (0.07 – 0.35mg/kg/hr in our patient). Our patient received no bolus and an infusion dose of 0.2mg/kg/hr for 95 hours, which is considered sub-anesthetic dosing, but is much higher than doses used for treatment of depression and moderately longer duration than is typical for pain. Ketamine’s psychomimetic properties in humans have been reported. Post anesthetic “emergence phenomena” may be seen at doses of 2mg/kg and have been described12 as “dream-like states, vivid imagery, hallucinations, and emergence delirium” and can be accompanied by “confusion, excitement, and irrational behavior.” These phenomena generally resolve within a few hours, though can take up to 24 hours. “Emergence phenomena” differ from our case in that patients are generally somnolent and in
a “state resembling cataplexy”, whereas our patient had increased goal directed activity and a reduced need for sleep, which took weeks to resolve. A literature search in PubMed using the terms “ketamine induced mania” was performed. Three cases of ketamine-induced mania were identified. One case8 describes a woman receiving 10-20mg/hr of ketamine (~0.1-0.4mg/kg) for pain who developed emotional lability and irritability within one day, on day 7. Similar to our case, she exhibited euphoria, pressured speech, flight of ideas, and tangentiality. Unlike our case, this patient had a history of possible post-operative hypomanic symptoms. Her infusion was terminated on day 11 and by day 20 her manic syndrome was resolving but hypomania persisted post discharge. The details of this case have been scrutinized and criticized.12, 13 The second case9 describes a patient with known Bipolar Disorder, who developed mania after a single ketamine infusion of 0.5mg/kg. Within 24 hours of treatment, she developed increased energy, hypersexuality, and impulsivity. She required psychiatric hospitalization for mood stabilization. Our case differs from this case because our patient had no history of Bipolar Disorder. The third case14 reported a patient with no history of Bipolar Disorder, who inhaled 5-15g/week of ketamine for 12 months and developed symptoms of mania that persisted for months after cessation of use. The dose and duration of ketamine used in our case was much lower than that used in this recreational ketamine case. Alternative causes of secondary mania should be considered, such as the emergence of complex partial seizures, hyperthyroidism, Cushing’s syndrome, and/or other implicated medications (ex. stimulants, corticosteroids, macrolides, quinolones, and metoclopramide). These were ruled out in our patient as his free T4 was within normal limits, his physical exam was negative for focal neurological deficits, and he was not given any medications that have been implicated in mania other than ketamine. Other factors could have contributed to the emergence of mania in this patient. For example, fentanyl has been reported15 to cause mania at doses of 15,000mcg, but our patient only received 100mcg, making this unlikely to be the cause. Moreover, our patient’s symptoms were unlikely to be due to opioid withdrawal as he remained on high doses of opioids throughout his hospitalization and his opioid dosing was increased, rather than reduced, when ketamine was started. It is possible that perioperative stress and uncontrolled pain could have been a contributing factor in development of mania, along with the ketamine infusion. Interestingly, ketamine is now being studied16 and employed in the treatment of Bipolar Depression. Researchers have evaluated12 “treatment emergent manic like symptoms” in patients with known Bipolar Disorder receiving ketamine, using the Young Mania Rating Scale. Transient mood elevation was noted in a minority of patients, lasting minutes to hours, and therefore contrasts with our patient as his manic symptoms took weeks to resolve. Although the duration and magnitude of these manic symptoms differ, mood elevation was noted after ketamine use in several patients and therefore lends credence to ketamine’s potential to induce mania. In summary, ketamine is known to cause symptoms of mania in animal models6, but definitive evidence in humans in lacking. This report adds a fourth case of possible ketamine induced mania to the literature, however this is the first case report of mania in a patient with no past history of manic or hypomanic symptoms. As ketamine is being increasingly used in psychiatric and non-psychiatric
populations, all providers should be aware of the possibility of an affective switch with the use of ketamine, either as an adverse medication effect, or as an unmasking of an underlying Bipolar Disorder. It is unclear if ketamine can induce mania in susceptible individuals, though this case suggests that it may.
References: 1. Laskowski K, Strilin A, McKay WP, Hyun JL. A Systemic Review of Intravenous Ketamine for PostOperative Analgesia. Can J Anesth. 2011;58:911-23. 2. Fine PG. Low-Dose Ketamine in the Management of Opioid Nonresponsive Terminal Cancer Pain. J Pain Symptom Manage. 1999;17:296-300. 3. Fang Y, Wang X. Ketamine for the treatment of refractory status epilepticus. Seizure. 2015 (Aug);30:14-20. doi: 10.1016/j.seizure.2015.05.010. Epub 2015 May 19. 4. Riedel WJ. The Ketamine Model of Positive, Negative, and Cognitive Symptoms in Schizophrenia: Facts and Frictions. J Psychopharmacol. 2007;21(3):235-6. 5. Corlett PR, Honey GD, Fletcher PC. From Prediction Error to Psychosis: Ketamine as a Pharmacological Model of Delusions. J Psychopharmacol. 2007;21(3):238. 6. Gazal M, Valente MR, Acosta BA, et al. Neuroprotective and Antioxidant Effects of Curcumin in a Ketamine-Induced Model of Mania in Rats. Eur J Pharmacol. 2014;724:132-9. 7. Mathew SJ, Shah A, Lapidus K et al. Ketamine for Treatment-Resistant Unipolar Depression: Current Evidence. CNS Drugs. 2012;26(3):189-204. 8. Ricke AK, Snook RJ, Anand A. Induction of Prolonged Mania During Ketamine Therapy for Reflex Sympathetic Dystrophy. Biol Psychiatry. 2011;70:e13-e14. 9. McInnes LA, James-Meyers MB, Turner MS. Possible affective switch associated with intravenous ketamine treatment in a patient with bipolar I disorder. Biol Psychiatry. 2015 Jul 7. pii: S0006-3223(15)00572-7. doi: 10.1016/j.biopsych.2015.07.003. [Epub ahead of print] 10. Murrough JW. Ketamine as a Novel Antidepressant: From Synapse to Behavior. Clin Pharmacol Ther. 2012;91(2):303-9. 11. Wang L, Johnston B, Kaushal A, Cheng D, Zhu F, Martin J. Ketamine added to morphine or hydromorphone patient-controlled analgesia for acute postoperative pain in adults: a systemic review and meta-analysis of randomized trials. Can J Anesth 2016; 63:311–325.
12. Niciu MJ, Luckenbaugh DA, Ionescu DF, et al. Subanesthetic Dose Ketamine Does Not Induce an Affective Switch in Three Independent Samples of Treatment-Resistant Major Depression. Biol Psychiatry. 2013;74:e23-e24. 13. Altinay M, Anand A. Reply to: Subanesthetic Dose Ketamine Does Not Induce an Affective Switch in Three Independent Samples of Treatment-Resistant Major Depression. Biol Psychiatry. 2013;74:e25. 14. Lu Y, Lin C, Lane H. Mania following ketamine abuse. Neuropsychiatric Disease and Treatment. 2016;12:237-239. 15. Medjugorac H, Horvat N. P.2.g.007 Fentanyl induced organic mania. European Neuropsychopharmacology 2011;21(s3):S444. 16. McCloud TL, Caddy C, Jochim J, Rendell JM, Diamond PR, Shuttleworth C, Brett D, Amit BH, McShane R, Hamadi L, Hawton K, Cipriani A. Ketamine and other glutamate receptor modulators for depression in bipolar disorder in adults. Cochrane Database of Systematic Reviews 2015, Issue 9. Art. No.: CD011611. DOI: 10.1002/14651858.CD011611.pub2.