Managing Lower Extremity Conditions In Patients With Mental Illness

Psychiatric disorders such as depression, schizophrenia and posttraumatic stress disorder can complicate the treatment of lower extremity conditions. Accordingly, this author details the potential for interaction between podiatric and psychiatric medications, critical perioperative considerations, issues with adherence and potential post-op dilemmas with lower extremity care in patients with mental illness.

Podiatric physicians provide interventions to improve the quality of life and physical activity of patients, but the emotional health of patients can be a key component in determining the outcome and quality of these treatments.

Research in numerous areas including spine, trauma, sports medicine, joint reconstruction and upper extremity surgery has shown a link between the emotional status of patients and functional outcomes. When patients are affected by mental illness, there is often a divide between subjective disability versus objective impairment that we can better explain by mood, stress and coping ability than by a pathologic process.

We need to consider several factors in the treatment of patients with mental illness. These factors include the specific psychiatric disorder, disorder severity, psychiatric treatment, medical comorbidities, potential drug interactions, perioperative management if surgical treatment is necessary and psychosocial considerations.  

Medical comorbidities. Patients with severe mental illness, namely severe bipolar disorder and psychotic illness, have increased mortality rates with the leading cause of death being cardiovascular disease.¹ Other common medical conditions of patients with severe mental illness include metabolic disorders, chronic pulmonary disease, gastrointestinal disorders and obesity.^2,3 Obesity, metabolic syndrome and diabetes also frequently occur in patients with mental illness due to a combination of poor lifestyle choices, weight gain from medications and inadequate access to quality care.^1,4

Pharmacologic considerations. While numerous non-pharmacological treatment options are available for mental illnesses, the majority of patients with mental illness take one or more psychoactive medications. In 2010, antidepressants were the third most common class of prescription drugs in the United States with reported use by 8.7 percent of the population.⁵ Interactions with other medications can increase or decrease the effectiveness of the psychoactive medication, or cause toxic effects. Cytochrome P450 metabolizes many psychoactive medications so caution is necessary with co-administration of other medications.⁶

Perioperative considerations. Psychiatric illness is a very important component of the perioperative management of patients. Psychiatric patients have an increased risk of perioperative complications due to impairment of their biologic response to stress.⁷

Depending on the type and severity of mental illness, preoperative considerations can include assessment of a patient’s decision making capacity and ability to obtain informed consent, his or her ability to follow pre- and postoperative instructions, coping mechanisms and social support. Additionally, podiatric physicians must consider the potential impact of psychoactive medications and other medical comorbidities during the perioperative period. Always consider psychiatric consultation for input regarding perioperative management of those with psychiatric illnesses and their current medications as well as assessment of the patient’s medical decision-making capacity and ability to give informed consent.  

Psychosocial considerations. Depending on severity, mental illness can compromise a patient’s ability to adhere to treatment regimens and continue follow-up care. Ng and colleagues performed a prospective observational study of patients with psychiatric disorders (schizophrenic, affective or schizoaffective disorders) undergoing orthopedic surgery.⁸ The authors found that 58 percent of patients defaulted for follow-up care and 45 percent had poor adherence with therapy regimens.

Poor adherence can lead to unsatisfactory outcomes and potentially serious postoperative complications. In this study, the authors also found poor family support and poor insight of patients into their condition, factors that can also contribute to poor adherence with treatment and follow-up care.⁸ Evaluating a patient’s understanding of his or her condition and treatment plans, as well as active involvement of the patient’s family in providing support and adherence with treatment and follow-up care are extremely important in the management of lower extremity injury in patients with mental illness.

The following is a review of several common psychiatric disorders, pharmacological considerations and their perioperative management.

Pertinent Insights On Potential Drug Interactions And Perioperative Advice For Patients Being Treated For Depression
Depression is the most common psychiatric disorder, affecting close to 10 percent of the population.⁹ Depression is characterized by depressed mood and diminished interest in most activity. It can include symptoms of weight and appetite changes, sleep disturbance, psychomotor agitation or retardation, fatigue, feelings of worthlessness, lack of concentration, and recurrent thoughts of death and suicidal ideation. There are numerous depressive disorders with major depressive disorder being the most common subtype.

The cause of depression is multifactorial with the pharmacologic treatment based upon brain deficiency and altered receptor activity of dopamine, norepinephrine and serotonin.⁷ We can divide antidepressant medications into five groups: selective serotonin reuptake inhibitors (SSRIs) and serotonin/norepinephrine reuptake inhibitors (SNRIs); tricyclic antidepressants; monoamine oxidase inhibitors (MAOIs); and atypical antidepressants.

Selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs). The most commonly prescribed classes of antidepressants are SSRIs and SNRIs.¹⁰ The SSRIs block serotonin reuptake and increase the level of serotonin available to bind postsynaptic receptors. The SNRIs similarly block serotonin and norepinephrine reuptake, increasing the levels of serotonin and norepinephrine available to bind postsynaptic receptors. These inhibitors have little effect on other neurochemical systems and have few side effects, making them the first-line choice for the treatment of depression.

Abrupt discontinuation of SSRIs and SNRIs can cause discontinuation syndrome, which includes the symptoms of nausea, headache, dizziness, chills, body aches, paresthesias, insomnia and electric shock-like sensation. Authors recommend that patients continue using SSRIs and SNRIs through the perioperative period to prevent discontinuation syndrome.^7,11

There is potential for SSRIs and SNRIs to interact with numerous medications. Some of the most clinically relevant interactions include a risk of increased sedation with use of benzodiazepines; adverse antiplatelet effect leading to bleeding risk when combined with warfarin and non-steroidal anti-inflammatory drugs (NSAIDs); and lower seizure threshold and higher risk of serotonin syndrome when combined with tramadol.^7,11

Tricyclic antidepressants. Tricyclic antidepressants were the most commonly used medications for the treatment of depression prior to the development of SSRIs. Their use has decreased significantly due to their side effect profile and toxicity risk with overdose. Tricyclic antidepressants prevent presynaptic reuptake of serotonin and norepinephrine but also have antimuscarinic, antihistaminergic and anti-a1-adrenergic effects.¹²

Tricyclic antidepressants manifest a number of important drug interactions, affect cardiac conduction, increase seizure risk and increase the risk of delirium. Given these risks, authors recommend discontinuing their use prior to surgery. Peck and coauthors suggested tapering these medications gradually over several weeks with five half-lives needed to ensure medication clearance.¹¹ Tricyclic antidepressants are highly metabolized by the cytochrome P450 hepatic enzyme and drugs that inhibit this enzyme can decrease the drugs’ metabolism, leading to toxic levels.

For podiatric physicians, clinically, the most serious drug interactions of tricyclic antidepressants include the following:

• cyclobenzaprine increases serotonin levels;
• antibiotics such as clarithromycin (Biaxin, AbbVie) and erythromycin impair hepatic metabolism and increase QT interval;
• the antibiotic linezolid (Zyvox, Pfizer) increases serotonin levels;
• antifungals such as fluconazole (Diflucan, Pfizer), ketoconazole and itraconazole (Sporanox, Bristol-Myers Squibb) increase QT interval; and
• ondansetron increases QT interval and serotonin levels.¹³

Many other medications can cause significant interactions with tricyclic antidepressants and one should check all interactions prior to prescribing a new medication in combination with a tricyclic antidepressant.

Monoamine oxidase inhibitors (MAOIs). Due to their high incidence of side effects, MAOIs are in infrequent use and typically limited to the treatment of atypical and resistant cases of depression. These medications inhibit the breakdown of monoamine neurotransmitters including serotonin and norepinephrine.

The MAOIs have known numerous food and drug interactions. Tyramine, found in food and beverages such as liver, fermented substances, alcohol and aged cheese, can lead to hypertensive crisis by increasing the release of norepinephrine, which causes blood vessel constriction. The MAOIs have potential interactions with numerous medications that are clinically significant to podiatric physicians. These include narcotic pain medications (fentanyl, buprenorphine, codeine, tramadol, hydrocodone, hydromorphone, morphine, oxycodone), antiemetic drugs (ondansetron, promethazine), linezolid, cyclobenzaprine and diphenhydramine. Local anesthetics and NSAIDs are safe in patients taking MAOIs.^7,14

Numerous other medications can cause significant interactions with MAOIs and one should check all interactions prior to prescribing a new medication in combination with an MAOI. Due to the potential complications of withdrawal, relapse and drug interaction, authors recommend consulting psychiatry and anesthesiology regarding the discontinuation of MAOIs in the perioperative period.¹¹

Atypical antidepressants. Atypical antidepressants include bupropion, mirtazapine and trazodone. Patients can use these medications alone or in combination with other medications for the treatment of major depressive disorder. Atypical antidepressants have the benefit of low toxicity and a low side effect profile. Bupropion inhibits dopamine reuptake and decreases norepinephrine activity. Mirtazapine blocks both presynaptic and postsynaptic alpha-2 receptors as well as serotonin receptors. Trazodone inhibits serotonin reuptake and serotonin transmitters. If patients are taking any of these three medications, one should avoid prescribing linezolid or cyclobenzaprine as these medications can increase serotonin levels.¹³

Bupropion lowers the threshold for seizures and can therefore interact with other medications that lower seizure threshold including systemic corticosteroids, carbapenems and fluoroquinolones.¹³ Through its effect on hepatic enzyme CYP2D6, bupropion can affect drug metabolism, leading to higher levels of antiemetic medications (promethazine), narcotic analgesics (hydrocodone, oxycodone, tramadol, morphine) and anticoagulants (warfarin).¹³ Trazodone can lead to QT interval prolongation when it is combined with several antibiotics and antifungals including clarithromycin, erythromycin, moxifloxacin (Avelox, Merck), fluconazole and itraconazole.¹³ Due to limited side effects and drug interactions, authors recommend continuing bupropion, mirtazapine and trazodone in the perioperative period.¹¹   

What You Should Know About Patients With Bipolar Disorder
Bipolar disorder is a mental disorder characterized by periods of elevated mood (mania or hypomania depending on the severity and presence of psychosis) and periods of depression. Mania is characterized by the symptoms of grandiosity, decreased need for sleep, fast/excessive talking, racing thoughts, distractibility, increased goal-focused activity and engaging in activity with potential for harmful consequences.¹⁵ Hypomania is characterized by similar symptoms but of a lesser degree and without associated psychosis. Depressive episodes are characterized by the symptoms of depressed mood, loss of pleasure or interest, weight and appetite changes, hypersomnia or insomnia, fatigue, feelings of worthlessness, loss of concentration, indecisiveness, and thoughts of death or suicide.¹⁵

There are numerous drugs for the treatment of bipolar disorder depending on the presence of manic, depressive or psychotic symptoms. The mood stabilizers lithium, valproate and carbamazepine are common for the treatment of bipolar disorder.

Lithium. The mechanism of action for lithium is not completely understood. In theory, it is believed that lithium enters excitable cells during depolarization, resulting in the reduction of the release of neurotransmitters in the central nervous system and peripheral nervous system.¹⁶

Research has also shown that lithium plays a neuroprotective role by inhibiting the N-methyl-D-aspartate receptor.¹⁶ The kidneys solely excrete lithium and the agent has a very narrow therapeutic window, necessitating regular monitoring of serum levels. Dehydration and decreased renal function both have the potential to increase lithium levels significantly, leading to toxicity. Symptoms of lithium toxicity include lethargy, restlessness, ataxia, dysrhythmias, renal failure and coma.¹⁷

Clinically significant drug interactions with lithium include linezolid (increases serotonin levels), aspirin (decreases lithium clearance), morphine (increases serotonin levels) and NSAIDs (decreases renal clearance).¹³ Non-steroidal anti-inflammatory drugs can increase lithium levels up to 40 percent, resulting in toxicity.¹⁸ Similarly, perioperative dehydration can also result in significant lithium toxicity so authors recommend discontinuing lithium 24 to 72 hours prior to surgery.^7,11

Valproate. Valproate is an anti-epileptic medication that physicians also use for the treatment of bipolar disorder. This medication functions through the inhibition of calcium and sodium channels in the central nervous system. Valproate can cause platelet dysfunction and increased bleeding risk. There is debate regarding the perioperative use of valproate and its use is dependent on factors including hematologic workup, plasma valproate levels and duration of therapy.¹⁹ Due to valproate’s potential to cause central nervous system depression, one should be cautious about combining this drug with other medications that cause sedation.¹⁸ Research has shown that several antibiotics increase valproate levels. These medications include cilastatin/imipenem (Primaxin, Merck), ertapenem (Invanz, Merck) and meropenem (Merrem, Hospira).²⁰

Carbamazepine. Carbamazepine is another anti-epileptic medication that physicians also use for mood stabilization in patients with bipolar disorder. Carbamazepine stabilizes voltage-gated sodium channels in the central nervous system, making fewer of these channels open and subsequently stopping the propagation of abnormal impulses in the brain.

Severe side effects of carbamazepine include bone marrow suppression leading to agranulocytosis and aplastic anemia.²⁰ Carbamazepine can cause numerous drug interactions through its effect on hepatic cytochrome CYP3A4. These interactions include benzodiazepines (decreased benzodiazepine level or effect), linezolid (increased linezolid toxicity), antibiotics (clarithromycin and erythromycin lead to increased carbamazepine levels), colchicine (decreased colchicine level), corticosteroids (decreased steroid level), hydrocortisone (decreased hydrocortisone level), and antifungals (increased carbamazepine levels).²⁰ Despite its side effects and numerous drug interactions, carbamazepine use usually continues in the perioperative period to ensure adequate control of the disease.¹¹  

A Guide To Medications, Side Effects And Potential Drug-Drug Interactions In Patients With Schizophrenia
Psychosis is an abnormal mental state involving loss of contact with reality. Schizophrenia is the most common psychotic disorder. Symptoms of schizophrenia include delusions, hallucinations, disorganized speech, abnormal behavior and negative symptoms including decreased emotional range, lack of speech, loss of interest and inertia.¹⁵ Schizophrenia causes significant functional impairment requiring multimodal treatment that consists of psychosocial therapies in addition to pharmacologic treatment. Treatment goals often aim at maintaining stability of symptoms, avoiding hospitalization and promoting social functioning.   

Antipsychotic medications. We can divide antipsychotic medications into two categories: typical (first-generation) and antitypical (second-generation) antipsychotics. Common typical antipsychotic medications include chlorpromazine, haloperidol (Haldol, Janssen Pharmaceuticals) and fluphenazine. These drugs are strong dopamine D2 antagonists and have additional effects of serotonin, alpha1, histaminic and muscarinic receptors. Typical antipsychotics frequently have extrapyramidal side effects including rigidity, bradykinesia, dystonia, tremor and akathisia.²¹ These medications also frequently cause tardive dyskinesia, involuntary movements of the face and extremities, and Parkinsonism.²¹

Common atypical antipsychotic medications include clozapine, olanzapine (Zyprexa, Eli Lilly), risperidone (Risperdal, Janssen Pharmaceuticals), amisulpride, quetiapine (Seroquel, AstraZeneca) and aripiprazole (Abilify, Otsuka America Pharmaceutical). These medications exert their effect by creating a dopamine D2 receptor blockade and additionally act on histamine, serotonin, muscarinic and alpha-adrenergic receptors. Atypical antipsychotic medications do not cause extrapyramidal side effects but they do cause adverse metabolic effects including weight gain, obesity, diabetes and hyperlipidemia.²¹ Both classes of medications are associated with adverse cardiac events, most notably QT prolongation.²¹  

When managing lower extremity conditions in schizophrenic patients, physicians need to consider numerous factors in determining ideal treatment plans. In terms of pharmacologic interventions, numerous drugs, most notably antibiotics, can interact with antipsychotic medications, leading to both increased and decreased antipsychotic drug levels.¹⁵

Given the potential for adverse cardiac events, one should avoid prescribing any drug that can cause QT prolongation in patients on antipsychotic medication.²² Agents causing central nervous system depression ­— including sedatives, antihistamines and antiemetic drugs — can have additive effects in patients using second-generation antipsychotic medications.²³ Authors recommend continuing antipsychotic medications during the perioperative period given the severity of the mental illness that these medications treat.¹¹ Given the potential for cardiovascular disease in this patient population as well as cardiac side effects of antipsychotic medications, one should obtain routine preoperative electrocardiograms on all patients with schizophrenia.¹¹ Strongly consider psychiatric consultation to aid in the perioperative management of these patients.

Keys To Recognizing Patients With Anxiety Disorders
Generalized anxiety disorder and panic disorder are among the most common mental disorders. These disorders are frequently accompanied by physical symptoms related to anxiety, leading patients to seek treatment. However, these disorders often go unrecognized and undertreated. Both disorders can negatively impact a patient’s quality of life and impact daily functioning.

Generalized anxiety disorder is characterized by excessive anxiety and worry, including the symptoms of restlessness, fatigue, lack of concentration, irritability, muscle tension and sleep disturbance. Panic disorder is characterized by the sudden onset of fear or discomfort. Symptoms include palpations, tachycardia, sweating, tremors, shortness of breath, choking sensation, chest pain, nausea, lightheadedness, sense of derealization or depersonalization, fear of losing control, fear of dying, paresthesias, chills and hot flashes.

What You Should Know About The Use Of Antidepressants And Buspirone For Patients With Anxiety Disorders  
Antidepressants are the first line of treatment for anxiety disorders. Treating physicians can also use benzodiazepines to treat anxiety disorders. Due to the potential for abuse, physical dependence and the development of tolerance, authors recommend only short-term use of benzodiazepines.²⁴ Given the benefits of reducing surgery-related anxiety and the potential for withdrawal, researchers recommend continuing benzodiazepines in the perioperative period.¹¹

Buspirone is another antianxiety agent that affects serotonin neurotransmission by functioning as a serotonin 5-HT1A receptor agonist. Given its sedative effects and benefit of reducing anxiety related to surgery, buspirone use should continue perioperatively.²⁵ Similar to other psychiatric medication co-administration with antibiotics and antifungals (clarithromycin, erythromycin, itraconazole, ketoconazole, rifampin), buspirone is contraindicated as these combinations can lead to impairment of hepatic metabolism and increased buspirone and benzodiazepine levels.²⁶ Another common interaction with buspirone is that co-administration with linezolid increases serotonin levels.²⁶

When Patients Have Posttraumatic Stress Disorder
Posttraumatic stress disorder (PTSD) is a pathologic anxiety response that occurs after an individual perceives a severe trauma or a threat to his, her or another individual’s physical safety or life. Originally classified as an anxiety disorder, PTSD is now considered a distinct separate disorder in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).¹⁵ Symptoms of PTSD include disturbing recurring flashbacks, avoidance, numbness, hyperarousal, negative thoughts persisting over one month following the inciting event.

Psychotherapy is the gold standard for the treatment of PTSD. Treating physicians use pharmacologic modalities to augment this therapy and manage many of the physiologic symptoms (insomnia, hyperarousal, emotional liability, anxiety) that can accompany this disorder.²⁷ The SSRIs and benzodiazepines are the most commonly used medications in the treatment of PTSD.²⁷

How Psychological Factors Can Influence Treatment Outcomes
There is a vastly growing body of evidence showing a strong relationship between psychological factors and outcomes following both conservative injury treatment and surgery.^28-32 Patients often have certain functional expectations following treatments or surgeries, and when treatment does not meet expectations, patients may be dissatisfied with the outcome of a technically successful procedure. Mental illness and a patient’s mental state at the time of injury or surgery can strongly contribute to his or her perception of the treatment outcome.

In the recent literature, Sivaganesan and colleagues examined numerous variables and found that pre-injection anxiety significantly decreased the odds of successful epidural steroid injections for lumbar spine pathology.²⁹ Several studies have shown that psychological factors and mental status can affect patient outcome and patient satisfaction with total hip and knee replacement procedures.^30,31,33,34 Similarly, several studies in the spine literature have shown that depression can negatively impact the outcomes of cervical and lumbar spinal injury and surgery.^32,35,36 Depression and depressive symptoms have also been associated with increased pain and decreased physical health following injury and surgery.^33-37  

Similar to depression, anxiety disorders have a strong influence on the treatment outcomes of lower extremity injury and there is a growing body of evidence suggesting that anxiety disorders play a role in the extent of injury and pain.^38,39 For example, patients with panic disorder are hypervigilant and can be very sensitive to adverse events, which can lead to maintenance of anticipatory anxiety in the treatment of injury or illness.⁴⁰ Patients with anxiety can have the tendency to catastrophize (tendency to expect the worst when pain is present), which can lead to guarding and increased disability during rehabilitation.⁴¹ Similar to findings in those with depression, studies have found that patients with severe anxiety have a risk of developing higher levels of postoperative pain and decreased response to treatment modalities.^29,33,39  

When PTSD, Depression And Anxiety Result From Injury And Surgery
There is a large body of evidence in the orthopedic and spine literature highlighting the incidence of depression, anxiety and PTSD following injury and surgery.^42-47 While PTSD is most commonly associated with military combat, the disorder reportedly occurs in 20 to 51 percent of patients with orthopedic injuries.48 Post-traumatic stress disorder is most common in surgery patients with a significant number of patients developing PTSD when their postoperative course is long or complicated.

A study conducted at the Oregon Health and Science University found that one in five patients undergoing lumbar arthrodesis develop postoperative PTSD.⁴⁶ Boer and coworkers found that 12 percent of patients whose initial procedure was complicated by secondary peritonitis developed PTSD symptoms.⁴⁹ The severity of injury does not correlate with the development of PTSD.⁵⁰ Two predictors of the development of PTSD following injury and surgery include a history of depression and acute stress response during hospitalization.^51,52

Depression and anxiety are relatively common complications of many injuries and surgical procedures. Oflazoglu and colleagues found that 12 percent of patients presenting to hand surgeons with upper extremity injuries met the diagnosis criteria for major depression.⁵³ The authors found the factors of multiple pain conditions, prior history of depression and activity limitations to be associated with a diagnosis of depression.

The development of depression and anxiety following surgery is complex and results from both physiologic and psychological processes. Numerous factors can contribute to the development of postoperative depression and anxiety including adverse effects of anesthesia and narcotic pain medication, pain, limitation of activity, lack of independence, and uncertainty about future function and ability.
Researchers have shown pain to cause alterations in synaptic connections and altered signaling in numerous areas of the brain contributing to the link between pain and depression.^54-56 Dysfunction in the serotonergic system also plays a strong role in depression and pain conditions.⁵⁷ Postoperative functional impairments have a strong impact on the development of postoperative depression and anxiety.⁵⁸ Researchers have found that a preoperative diagnosis of depression or anxiety is the strongest predictor of postoperative depression.⁵⁹

Numerous studies have shown postoperative depression following cardiac, bariatric surgery and spine surgery, but there are relatively few studies examining the psychological effects of foot and ankle surgery.^60,61 McPhail, van der Sluis and their respective co-authors have reported that ankle fractures have long-term psychological as well as physical effects similar to more severe injuries including polytrauma, hip fracture and spine fracture.^62,63 They noted that psychological complications of ankle fractures include fatigue, depression, anxiety and sleep disturbances.

In Conclusion
Further research is needed to examine the effect of mental illness on the outcomes of conservative and surgical treatment for lower extremity conditions. Currently, there is very little information on how to adequately address the conservative and surgical management of lower extremity injury in patients with mental illness. Physicians need to improve their ability to recognize comorbid psychiatric disorders in their patients. In order to help improve patient coping mechanisms and adherence, physicians need to enlist family and community support, and work with psychiatric services. In order to address the complexities that can arise in the management of patients with mental illness, comprehensive care plans with integrated teams of healthcare providers should develop to optimize treatment outcomes and minimize potential complications.

Dr. Hoffman is in private practice in Boulder, Colo. She is the Chief of the Surgery Section at Boulder Community Hospital in Boulder, Colo. Dr. Hoffman is a Fellow of the American College of Foot and Ankle Surgeons.

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