Pharmacologic Approach to the Psychiatric Inpatient
Arash Ansari
David N. Osser
Leonard S. Lai
Paul M. Schoenfeld
Kenneth C. Potts
Characteristics of Inpatient Treatment
The role of inpatient psychiatric treatment has evolved in recent decades. Psychopharmacologic advances have enabled more successful treatment of major mental illnesses. The movement to deinstitutionalize psychiatric patients and shift care to community-based agencies and the economic realities of the health care marketplace have had major impact to reduce the length of stay. Nevertheless, a recent study by the U.S. Health and Human Services Agency for Healthcare Research and Quality1 found that in 2004, 1.9 million out of 32 million admissions (6%) to US community hospitals were primarily for a mental health or substance abuse diagnosis, while an additional 5.7 million admissions (18%) also involved depression, bipolar disorder, schizophrenia, or other mental health diagnoses or substance abuse-related disorders as a secondary diagnosis. The top five diagnoses reported were mood disorders, substance abuse-related disorders, delirium/dementia, anxiety disorders, and schizophrenia. The average length of stay for a patient with a primary mental health or substance abuse diagnosis was 8 days compared to 5 days for nonmental health-related diagnoses.
Because of time limitations, the goals of inpatient psychiatry have shifted from striving to achieve full remission to symptom alleviation through the judicious use of psychotropic medication so that the stay can be brief. Patients may therefore be discharged as long as they are evaluated to be unlikely to harm themselves or others, even though only some of the most distressing symptoms have improved, for example, agitation, anxiety, or insomnia. Medication treatment plans focus on these symptoms with the understanding that the full effect and benefit may not occur for several weeks. Psychosocial treatments such as intensive short-term individual psychotherapy, group therapy, and milieu interventions that apply the principles of psychodynamic, cognitive, behavioral, and dialectic behavioral techniques are vital in helping patients reduce problematic thoughts, behavior, feelings, and other responses to their stressors and symptoms in the inpatient setting. As no patient exists in a vacuum, outreach to families, significant others, and social supports to address possible acute psychosocial precipitants will contribute to helping reduce the likelihood of a relapse or a recurrence. Consultations with outpatient providers can be of critical importance. The inpatient stay can often provide an opportunity to clarify how the community treatment network can be made more efficient and responsive to the patient’s needs.
Factors Influencing Pharmacotherapy on an Inpatient Unit
Publicly and privately funded inpatient psychiatric treatment is usually authorized for patients who present a danger to themselves or to others or who have demonstrated that they are unable to care for themselves. Inpatient treatment is monitored closely by mental health review agencies hired to ensure that this most expensive level of psychiatric care is used effectively and minimally in order to contain costs. Inpatient treatment teams must be vigilant about the time limitations imposed on
each admission. This is made more difficult by the fact that the safety concerns that open the door to an inpatient admission generally are often found to be complicated by a myriad of additional reasons for which the patient has come to the attention of health care providers. Thorough assessment and formulation of why the patient is in a crisis must be done quickly and with a careful evaluation of which symptoms and contributing factors are the most important to address. These factors can range from noncompliance with treatment because of poor insight to limited treatment access and to destabilizing forces such as homelessness and family or relationship conflicts. Patients have comorbid medical illnesses or substance abuse-related factors that confound and prevent successful outpatient interventions. Therefore, the challenge for the inpatient multidisciplinary treatment team is to be able to evaluate and stabilize the sickest patients in the psychiatric care continuum in the shortest time possible.
each admission. This is made more difficult by the fact that the safety concerns that open the door to an inpatient admission generally are often found to be complicated by a myriad of additional reasons for which the patient has come to the attention of health care providers. Thorough assessment and formulation of why the patient is in a crisis must be done quickly and with a careful evaluation of which symptoms and contributing factors are the most important to address. These factors can range from noncompliance with treatment because of poor insight to limited treatment access and to destabilizing forces such as homelessness and family or relationship conflicts. Patients have comorbid medical illnesses or substance abuse-related factors that confound and prevent successful outpatient interventions. Therefore, the challenge for the inpatient multidisciplinary treatment team is to be able to evaluate and stabilize the sickest patients in the psychiatric care continuum in the shortest time possible.
In some cases, keeping the inpatient stay brief may be therapeutic, especially in the more character-disordered where the inpatient treatment milieu may encourage regressive behaviors.
Goal of Inpatient Treatment as Related to Pharmacotherapy
The task of the psychiatrist is to alleviate some of the presenting symptoms. This may mean the commencement of a new medicine or the resumption or adjustment of a medication regimen that has been effective in the past. The choices made have to enable prompt and effective symptom relief while the patient is in the hospital and to be feasible for the outpatient treatment team to continue in the community. Some medicines will be effective in the short run, for example, benzodiazepines for anxiety, whereas other medicines such as antidepressants are initiated with the expectation that in time a more definitive effect will occur. In other situations, it may be preferable to withhold initiation of pharmacologic treatment, such as when the presenting picture is complicated by significant substance abuse that obscures determination of whether Axis I pathology is primary or secondary. The opportunity to observe the initial response to medication will also allow evaluation of side effects, such as excess sedation or akathisia, which may preclude the use of that particular drug.
Close observations by the treatment team facilitate psychopharmacology decisions dependent on symptoms rather than syndromal diagnoses. For example, medicine may be given to target anxiety symptoms while it is determined if the symptoms are part of a mood disorder or an independent anxiety disorder.
It is important to explain to the patient and his or her family that the short length of stay allowed does not commonly result in full remission. They need to understand that the goal is to reduce troubling symptoms and to enable the patient to feel safer, be in better behavioral control, and to be able to function better with or without the assistance of others in the community. Often the suicidal or homicidal ideation that prompted the admission will resolve soon after admission because of the containment and structure of the supportive inpatient milieu. The focus will then quickly shift to the crucial question of whether the patient still requires inpatient level of care.
Selecting Treatment
Selecting initial psychopharmacologic treatment for a newly admitted patient can be a complicated process and is based on multiple considerations and variables. Often the prescribing physician must weigh many of these variables simultaneously and rapidly given the complicated psychiatric, medical, and psychosocial presentations of most hospitalized patients. Ten factors that influence choice of initial agent will be reviewed.
SYMPTOM CONTROL—THE AGITATED PATIENT AND THE USE OF P.R.N. MEDICATION
The inpatient psychiatrist is faced with the challenge of making a provisional diagnosis and an initial treatment plan for the patient. Sometimes this diagnosis is based on very limited or even contradictory clinical and historical data. The clinician must be aware that new information may come to light, and
the diagnoses may need to be modified. Recalling the guiding principles of “safety first” and “do no harm” is frequently helpful.
the diagnoses may need to be modified. Recalling the guiding principles of “safety first” and “do no harm” is frequently helpful.
It is important to identify and treat the most serious symptoms regardless of diagnosis—these include violence, aggression, assault, self-harm, suicide, disorganizing psychosis, agitation, and risk of dying from inanition or other complications of poor oral intake and immobility (e.g., deep venous thrombosis [DVT], aspiration pneumonia, and skin breakdown). A symptom-based approach to psychopharmacologic treatment in an inpatient setting is therefore often necessary. This section will focus on the treatment of the agitated patient and the use of p.r.n. medication.
The Agitated Patient
A patient may become agitated at any time during the admission. Upon entry to the hospital, factors include the effects of being confined, the change in environment, and the loss of autonomy. A patient may become agitated later in the admission, such as if too rapidly allowed out of a contained situation or denied privileges. Nicotine-dependent patients can become extremely agitated if not permitted to smoke when they want. Interestingly, a recent study found that when units become smoke-free, incidents of agitation and restraint are markedly reduced.2
The violent, aggressive, or out-of-control patient can be very difficult to manage. The risk of assault or of self-harm must be assessed and reassessed. Prevention is the best approach, of course, with active treatment of any patient who may be at risk.
Certainly, the intensive use of the structure of the inpatient milieu can be instrumental in minimizing the need for medication. The containment of quiet rooms and destimulation can reduce potentially stressful situations for the patient, allowing time for a treatment plan to help an agitated patient.
However, there are situations where all the best efforts fail. Safety of the patient or staff is at risk, and sometimes urgent medication is necessary. When a rapid response is required, parenteral medication is indicated (although in less acute situations oral medication should be considered). A combination of an intramuscular typical antipsychotic and a benzodiazepine has been shown to be more effective than either one used alone.3 This combination can avoid the need for an adjunctive dose of an anticholinergic; extrapyramidal symptoms (EPS) are infrequent. The advantages are avoiding both additional injections and anticholinergic toxicity. A common combination includes haloperidol 2 to 5 mg along with lorazepam 1 to 2 mg intramuscularly (in the same syringe) given every 30 to 60 minutes, up to three doses. Haloperidol is often considered first-line because of its relative safety profile, the lack of an established ceiling dose, and years of clinical experience. Other typical antipsychotics are less often used in this situation and have become less available. Intramuscular chlorpromazine is not recommended because of its high risk of hypotension. Intramuscular droperidol should not be used in the emergency treatment of agitation because of the increased risk of QTc prolongation with this agent.
The role of intramuscular atypical antipsychotics (i.e., ziprasidone, olanzapine, aripiprazole) is less clear. The upper limit of dosing and risks of drug interactions (e.g., QTc prolongation issues) may preclude ongoing use in an agitated patient. Although these drugs are heavily promoted by their manufacturers and many clinicians use them, the evidence base is unsatisfactory. All have been compared with haloperidol alone, without lorazepam or concomitant anticholinergic agents.4, 5, 6 This gave the atypicals an unfair advantage.
One alternative to consider is monotherapy with parenteral lorazepam. This can be a valuable option when exposure to a typical antipsychotic is undesirable. A usual dose may be 1 to 3 mg intramuscularly hourly up to three doses. Some clinicians may be hesitant to use benzodiazepines with a substance-using patient. However, its efficacy in treating agitation in an emergency may well outweigh these concerns. Some clinicians are also concerned about the risk of “disinhibition” or a paradoxical reaction. There are no clear risk factors for this, and it appears to be rare. The risk of respiratory depression with repeated doses of benzodiazepines should be taken into account, especially if the patient has other sedating drugs on board, or has pulmonary insufficiency. As with all medication, an elderly agitated patient may require significant dose reduction and greater intervals between dosing.
Use of p.r.n. Medication
The use of so-called p.r.n. medication (pro re nata—“as the thing is born”) is common in inpatient psychiatry to treat a variety of symptoms, including agitation (see preceding text), anxiety, breakthrough
psychotic symptoms, and insomnia. Judicious use of p.r.n. medication can be very helpful in evaluating the need to change the standing medication plan. For example, the psychotic patient who is not “held” by his standing medication and needs “extra” doses may need a reevaluation of the standing medication dose.
psychotic symptoms, and insomnia. Judicious use of p.r.n. medication can be very helpful in evaluating the need to change the standing medication plan. For example, the psychotic patient who is not “held” by his standing medication and needs “extra” doses may need a reevaluation of the standing medication dose.
However, there are also potential pitfalls. There is the risk of forming an association, on the part of the patient, between an undesirable behavior and taking an extra pill, thereby reinforcing drug-seeking behavior and externalization of responsibility. On many units, the culture is to actively encourage patients, if in distress, to ask for a p.r.n. medication. The astute clinician then helps the patient identify the precipitating factor and solve the problem, thereby fostering more of a sense of self-control on the part of the patient.
The milieu effect of p.r.n. medication is important to consider. Asking for extra medicine may be a patient’s way of communicating the need for more contact, especially in a busy inpatient unit. The patient may then feel heard, attended to, and held, even if medicine is not offered. The interaction allows for more patient-staff contact. In addition, nursing staff often feel safer if p.r.n. medication is “on the books” for a challenging patient. The placebo effect of p.r.n. medication must not be overlooked.
The choice of a p.r.n. agent should take into account the relevant symptom and the current medication list. Attention should be paid to the total daily dose (standing plus p.r.n. available) so as to avoid exceeding maximum recommended doses. When treating psychosis or mania, p.r.n. medication should ideally be the same as the standing medication, so as to avoid the risks of polypharmacy, including the risks of adverse (e.g., cardiac) effects. Adjunctive use of benzodiazepines can be very helpful in psychotic patients.3
In patients with anxiety, short-acting or intermediate acting benzodiazepines are often used. Although not approved by the U.S. Food and Drug Administration (FDA), many clinicians use low-dose antipsychotics in these patients, especially if substance abuse is an issue. Low-dose antipsychotics may be particularly helpful in patients with anxiety or agitation associated with personality disorders7,8 (see subsequent text). Trazodone is a cost-effective alternative that needs further study. Prazosin can be useful as a p.r.n. during the day for patients with post-traumatic stress disorder (PTSD) as well as at night for sleep.9,10
Insomnia is probably the single symptom for which p.r.n. medication is most frequently requested. Insomnia may be due to the environment, a side effect of medication, a complication of a general medical condition (such as restless legs syndrome [RLS] or obstructive sleep apnea), a consequence of excessive intake of caffeine or nicotine, a symptom of withdrawal, and so on. Although sleep hygiene should be addressed, often medication is required. Choices include antihistamines, benzodiazepines, trazodone, low-dose sedating tricyclic antidepressants, prazosin, and newer hypnotics.
Psychotropic medicines, both p.r.n. and standing, also play a crucial role in the treatment of patients with borderline personality disorder (BPD). Often patients with BPD are admitted to inpatient units when they are emotionally overwhelmed, regressed, and in poor behavioral control. Heightened emotional lability, irritability, anger, impulsivity, transient psychosis, and agitation can all be present. Frequently p.r.n. medicines are used to decrease the intensity of these symptoms, and, if helpful, may be continued as standing treatment. When the patient with BPD exhibits dangerous agitation that places the patient or others directly at risk of harm, then, as is the case in the schizophrenic or manic patient, intramuscular or oral antipsychotics are likely to be needed. Overall total doses needed are usually less than those employed in manic or psychotically agitated patients. Even when immediate dangerousness is not an issue, antipsychotics can be used to decrease patient hostility and transient psychosis.11 Although there is no reason to believe that any one antipsychotic is more effective than any other, in acute situations many clinicians prefer to use an antipsychotic that can have immediate and observable effect (e.g., perphenazine, haloperidol, or risperidone). Quetiapine is also frequently used for p.r.n. treatment of anxiety in patients with BPD. Disinhibition from benzodiazepines (which as previously noted is of limited concern when treating violent behavior in general) is of particular concern in patients with BPD and may lead to further behavioral dyscontrol;12 benzodiazepines, therefore, should not be used to treat anxiety in these patients. Once acuity has decreased and transient psychotic phenomena have subsided, continuing an antipsychotic as a standing medication may help reduce impulsivity and aggression, and improve overall functioning.13 Again, total doses needed are usually lower than those needed for the ongoing treatment of a primary psychotic disorder.14,15 Quetiapine and aripiprazole may also be helpful for ongoing mood and anxiety symptoms in these patients.8,16 Serotonergic antidepressants
and mood stabilizers may help primarily with affective lability and anger.11,13 One controlled study of 30 patients suggested that omega-3 fatty acids may reduce depression and aggression in patients with moderate BPD.17 On the other extreme with respect to toxicity, clozapine has been reported in several uncontrolled studies to be helpful in reducing morbidity in some treatment refractory patients.18,19
and mood stabilizers may help primarily with affective lability and anger.11,13 One controlled study of 30 patients suggested that omega-3 fatty acids may reduce depression and aggression in patients with moderate BPD.17 On the other extreme with respect to toxicity, clozapine has been reported in several uncontrolled studies to be helpful in reducing morbidity in some treatment refractory patients.18,19
PATIENT’S PSYCHOPHARMACOLOGIC HISTORY
An advantage the inpatient psychiatrist has is extended time to obtain a history of the psychopharmacologic treatment the patient has received. It is time well spent. The psychiatrist should have several interviews with the patient over a few days to ascertain as much detail as possible about what the patient remembers about his medication history. Information about dose, efficacy, side effects, duration of treatment, and use of different medication combinations is necessary to formulate an approach and apply relevant treatment algorithms. The level of functional recovery with previous treatment interventions is critical to assess. An understanding of the factors that contribute to compliance or noncompliance is essential for establishing the ongoing medication treatment alliance. Repeating treatment trials that have failed in the past is to be avoided if possible. It is important to obtain a comprehensive list of all prescribed and over-the-counter medicines used by the patient for general medical ailments to evaluate for possible drug interactions.
Careful medication reconciliation on admission is required. The physician must accurately determine what the patient was taking immediately before admission. For each identified item, there should be clear documentation of the plan to continue, change, or stop the medication. This practice promotes the accurate administration of medication.
Because the patient may be an unreliable informant, collateral information from outpatient clinicians and family members should be actively sought as soon as possible. They often have critical insights and observations about how effective different psychopharmacologic interventions have been.
When medical records are available to supplement the data collected from patients and significant others, history gathering is easier. Fortunately, more and more health care organizations are switching to electronic information systems that enable all clinicians to have fast, convenient, and accurate access to psychiatric and general medical histories at the touch of a keyboard. However, when the patient is treated in multiple unrelated health care systems, it can still be extremely difficult to obtain accurate, sequenced historical information in a timely manner for a short inpatient stay. Error-prone educated guesswork can often not be avoided especially in the early days of an admission.
PREEXISTING GENERAL MEDICAL CONDITIONS
There are certain common general medical concerns that influence the selection of pharmacologic agents. Very early in the decision-making process, many physicians first glance at the patient’s past medical history to clarify the “medical milieu” in which they will be prescribing. Rapid access to laboratory data as well as other testing (e.g., electrocardiogram [ECG]), and review of general medical history especially in an electronic medical record, when available, are extremely helpful.
Cardiac
Many psychotropics can affect cardiac conduction, with the potential to delay conduction enough to lead to fatal arrhythmias. There is an association between sudden death and the use of antipsychotics20 and tricyclic antidepressants at high doses21 (but not selective serotonin reuptake inhibitors [SSRIs]), although causality has not been completely established, and there may be multiple etiologies. The cardiovascular effects of psychotropics should therefore be taken into account before beginning treatment.
Prolonged QT interval (reported as QTc when corrected for heart rate) is believed to be associated with torsades de pointes, a potentially fatal ventricular arrhythmia. The QT interval includes both the QRS interval as well as the ST segment. Whereas QRS (depolarization phase) lengthening is primarily associated with the use of tricyclic antidepressants (or low-potency typical antipsychotics with tricyclic structure) and their effect on sodium channels, atypical antipsychotics may potentially prolong the ST segment (repolarization phase) through their effect on potassium channels.22 Although there is some question whether QT prolongation is a reliable indicator for the risk of torsades de pointes,23 measuring this interval is the simplest way to estimate this risk.
Antipsychotics are not equal in their potential to affect the QT interval. Thioridazine, mesoridazine, pimozide, and droperidol24 have shown significant potential to prolong QT and should generally be avoided. Among the newer antipsychotics, ziprasidone is considered to have the greatest potential to lengthen QT.22 Some postmarketing studies such as the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) have not confirmed this.25,26 Premarketing data with aripiprazole indicate little risk.27 Clozapine may contribute to QT prolongation primarily in patients with other risk factors.28 The other cardiac risks of clozapine, that is risk of developing myocarditis or cardiomyopathy, are etiologically independent of its effect on cardiac conduction.
Tricyclic antidepressants, especially at high doses (particularly in the setting of overdose), have long been known for their potential to interfere with cardiac conduction and have traditionally been used with caution in patients with cardiac disease. Lithium may worsen sick sinus syndrome, produce blockade of the sinoatrial node, and also prolong QT.29 SSRIs do not appear to significantly prolong QT, although there has been concern regarding their potential to induce bradycardia.30, 31, 32
Patients at higher cardiac risk should be identified before starting treatment with antipsychotics, tricyclic antidepressants, and lithium. Caution should be used in the care of the elderly, those with preexisting cardiac disease or preexisting QT prolongation, bradycardia, hypokalemia, or hypomagnesemia, and in those taking concomitant medication with proarrhythmic potential. A baseline ECG should be obtained in these patients; if the QTc is >440 to 450 msec, the patient should be monitored more carefully, and a QTc >500 msec should greatly increase concern for arrhythmias. Ziprasidone is contraindicated if the QTc is >500 msec. Magnesium and potassium abnormalities should be corrected early on. In high-risk patients, medicines with lower potential for cardiac toxicity should be used, and an effort should be made to use the lowest effective dose. Additionally, the clinician should be aware of medication interactions that may increase the serum level of the selected agent (see section on Medication Interactions). The clinician should also consider obtaining repeat ECGs on any patient who is being treated with two or more psychotropics with high risks of QT prolongation as the doses of these medications are titrated.
Blood Pressure
Many commonly used psychotropics have α-adrenergic blocking effects and can therefore lower blood pressure. Some of the observed cases of sudden death in patients taking antipsychotics or tricyclic antidepressants may be primarily due to severe hypotension rather than to cardiac arrhythmias. Vital signs, commonly checked on admission and daily thereafter, can identify those with preexisting hypotension. Patients at risk for orthostatic hypotension include the elderly, those with cardiac disease, and those taking other medicines that can lower blood pressure. Medicines whose propensity to lower blood pressure mandates caution are clozapine, chlorpromazine, risperidone, quetiapine, tricyclic antidepressants, and trazodone. Clozapine, which carries the highest risk of causing orthostasis, requires a very gradual and careful titration (i.e., starting at 12.5 mg once or twice a day with increases starting with 25 mg increments daily). In the patient who has been noncompliant it should not be restarted at prior doses if treatment has been interrupted for 2 or more days. Chlorpromazine administered intramuscularly or at sudden high oral doses carries a similar risk. Although tolerance to this side effect usually develops, care should be exercised when starting these medicines (or restarting them at previously prescribed high doses in patients who may have been recently nonadherent to their regimen). Increased fluid intake should be encouraged as tolerated and orthostatic blood pressure should be monitored in symptomatic patients until the appropriate dose is reached.
In regard to the risk of increasing blood pressure, there has been concern regarding the use of serotonin and norepinephrine reuptake inhibitors (SNRIs) in patients at risk for hypertension. Venlafaxine used at high doses can increase blood pressure.33,34 This effect may be less pronounced with duloxetine and may not be clinically significant.35,36 Patients with stable, effectively treated hypertension have not been found to show an increase in blood pressure from venlafaxine.37
Hepatic
There are two considerations regarding choice of psychiatric drug in a patient with compromised hepatic function. The first is the issue of hepatotoxicity with certain medicines, and the second is the
use of hepatically metabolized agents in patients with preexisting liver disease. Baseline liver function tests should be measured, and if high, should influence care when using certain psychotropics.
use of hepatically metabolized agents in patients with preexisting liver disease. Baseline liver function tests should be measured, and if high, should influence care when using certain psychotropics.
Valproate, olanzapine, and quetiapine can cause hepatotoxicity. Although in the vast majority of cases any elevation in transaminases is mild and transient, these medicines should be used cautiously. The presence of clinically active liver disease or cirrhosis would suggest use of other agents (e.g., lithium rather than valproate for mania). If, during early inpatient treatment, transaminase levels increase to more than three times the upper end of the normal range, discontinuing or decreasing the dose of the offending agent should be considered. Patients with previous exposure to hepatitis B or C virus who are not acutely ill can still be treated with these medicines, although transaminases should be carefully monitored.38,39 Given the concern that one would be exposing these patients with potentially worsening liver disease to yet another toxic insult, alternative nonhepatotoxic agents (e.g., lithium) should be considered when appropriate. Valproate may also rarely cause hyperammonemic encephalopathy without causing transaminase elevation,40 although this is controversial.41
In the case of a patient admitted with preexisting liver disease, medicines which are primarily hepatically metabolized should be started at lower doses and increased slowly and agents with shorter half-lives should be used preferentially.
Renal
Measurement of kidney function, that is serum creatinine, is routinely done upon admission to an inpatient unit. Lithium, topiramate, and gabapentin are cleared by the kidneys, and any decrease in renal function warrants dose reduction of these medicines.
A common scenario is the admission to the inpatient unit of a patient whose lithium has been discontinued as an outpatient, because of concerns regarding worsening renal function (as can occur in up to 20% of patients on long-term lithium treatment).42 Often the patient had been previously well maintained for many years on lithium. Once lithium is discontinued, however, the patient may decompensate and require multiple alternative medication trials and multiple hospitalizations for recurrent manic or depressive episodes. In these patients, the overall risks of morbidity and mortality may be less with rechallenge with lithium than if lithium treatment is withheld. After a clear risk and benefit assessment, and in close consultation with a nephrologist, it may be clinically appropriate for these patients to resume taking lithium. Close monitoring from then on, while avoiding further episodes of lithium toxicity, and administration of lithium once a day at bedtime, may decrease the risk of worsening renal effects.43
Metabolic Syndrome
Metabolic syndrome is characterized by dyslipidemia, hyperglycemia, and weight gain and is a major risk associated with some second-generation antipsychotics.
Hyperglycemia/Diabetes
The prevalence of diabetes is higher in patients with schizophrenia (in part because of unhealthy lifestyles) independent of treatment with antipsychotics.44 Clozapine and olanzapine have clearly been implicated in increased risk of onset of hyperglycemia and diabetes, and in the exacerbation of preexisting diabetes, even leading to diabetic ketoacidosis. The propensity of quetiapine to cause hyperglycemia is numerically greater than that of other second-generation antipsychotics but less than that of the two agents mentioned earlier.25 The data regarding risperidone are mixed.45 One putative mechanism is that some of these agents rapidly induce insulin resistance, with or without causing weight gain.
Measuring fasting plasma glucose and inquiring about a patient’s personal and family history of hyperglycemia and/or diabetes can help identify those at risk for developing diabetes, and determining hemoglobin A1c can provide a measure of recent glycemic control. In patients at high risk of developing diabetes, aripiprazole or ziprasidone should be considered.46 If fasting glucose is elevated, a glucose tolerance test has excellent predictive value regarding who is going to develop overt diabetes.47
Weight Gain
The risk of significant weight gain, particularly in the first few months of treatment, should be considered when prescribing atypical antipsychotics. A 2- to 3-kg weight gain early in the course of treatment (i.e., within the first 3 weeks) often predicts the risk of substantial weight gain over the long term.48 However, different antipsychotics are not equal in their propensity to cause obesity. Clozapine and olanzapine are generally considered to be more likely to cause weight gain than quetiapine and risperidone, and in turn aripiprazole and ziprasidone are the least likely to contribute to weight gain.49 Measuring baseline body mass index (BMI) and waist circumference are recommended by recent guidelines.46 A patient’s admission weight must be measured to establish a pretreatment baseline.
Hyperlipidemia
Antipsychotics that have the highest propensity to cause weight gain also carry the highest risk of worsening lipid profile. Risperidone may be more neutral in this regard, and ziprasidone may actually improve lipid profile.25 Triglycerides are the lipids most affected by the use of atypical antipsychotics.50 A fasting lipid profile can identify those patients already at higher cardiac risk and again serve as a pretreatment baseline. Pharmacotherapy of hyperlipidemia may be necessary. Also education on diet and lifestyle changes necessary to manage these side effects is essential, although compliance with these changes over time can be more unsatisfactory than compliance with the antipsychotic treatment itself.51
Leukopenia, Thrombocytopenia
Although many psychotropics (e.g., antipsychotics) can cause leukopenia, clozapine and carbamazepine are the primary medicines that need to be avoided in leukopenic patients. Of the antidepressants, mirtazapine may be associated with leukopenia, although causality has not been established and this has been rarely observed in clinical practice.52 Gabapentin can also infrequently have a mild leukopenic effect.27 Lithium, on the other hand, has been suggested for treatment of leukopenia and may be beneficial in this regard;53 the mechanisms for increased white blood count may include demarginalization of neutrophils as well as possible release of colony-stimulating factors.54, 55, 56
The use of mood stabilizers such as carbamazepine, oxcarbazepine,57 and valproate58,59 is problematic in patients with preexisting thrombocytopenia because of their potential for lowering platelet count. Even when platelet count is normal, valproate may cause platelet dysfunction and prolong bleeding time.60,61 Therefore, patients taking valproate should be assessed for bleeding risk before any invasive surgical procedures.
Hyponatremia
The syndrome of inappropriate antidiuretic hormone secretion (SIADH), resulting in hyponatremia, has been documented in patients, especially the elderly, who have been taking antidepressants. In addition to SSRIs, mirtazapine, duloxetine, and bupropion have all been implicated.62, 63, 64 Among mood stabilizers, carbamazepine and oxcarbazepine can both cause hyponatremia,65 although the mechanism is not secondary to SIADH and is not well understood.66
Neurologic Disease
Seizures
Patients with seizure disorders provide challenges in the choice of medication. Antidepressants and antipsychotics are thought to lower seizure threshold and this effect is generally dose dependent.67 The most likely to do so are clozapine, chlorpromazine, olanzapine, quetiapine, tricyclic antidepressants, and bupropion (contraindicated in patients with seizure disorders). The risk with monoamine oxidase inhibitors (MAOIs) and SSRIs and other new antidepressants are considered to be low.68 This is controversial, however. Depression itself appears to increase seizure risk and a review of FDA clinical trial data for antidepressants has shown a possible anticonvulsant effect of newer antidepressants at
therapeutic doses69 (although in overdoses antidepressants are still considered to increase seizure risk). Among antipsychotics, haloperidol and risperidone are less likely to affect seizure threshold.70 All psychotropics should be used cautiously in patients with seizure disorders or when patients are seizure-prone (e.g., during alcohol or benzodiazepine withdrawal).
therapeutic doses69 (although in overdoses antidepressants are still considered to increase seizure risk). Among antipsychotics, haloperidol and risperidone are less likely to affect seizure threshold.70 All psychotropics should be used cautiously in patients with seizure disorders or when patients are seizure-prone (e.g., during alcohol or benzodiazepine withdrawal).
Stroke
Antipsychotics increase the incidence of stroke in patients with dementia.71, 72, 73 First- and second-generation antipsychotics likely pose equal risk.74 Possible etiologies for stroke may be related to cardiovascular effects or changes secondary to excessive sedation. In patients with dementia and significant behavioral dyscontrol or assaultiveness, SSRIs,75 trazodone, or mood stabilizers should be considered.76 However given their more rapid onset of action, antipsychotics should not be withheld if there is imminent risk of harm secondary to behavioral dyscontrol. The clinician should be aware that the use of both typical and atypical antipsychotics may be associated with an increased risk of death in patients with dementia.71
Extrapyramidal Symptoms
Patients with a prior history of dystonic reactions or substance abuse, and young, male patients are at higher risk for developing acute dystonias. Dystonias are primarily caused by typical antipsychotics but can occur with any antipsychotic with higher D2 receptor occupancy (e.g., risperidone). Olanzapine, especially in high doses, can also cause EPS, although at lower rates than typical antipsychotics, possibly because of its own anticholinergic effects.45 Quetiapine and clozapine are least likely to cause dystonias and parkinsonism.
Clozapine should also be considered in a patient presenting with tardive dyskinesia (TD), although all antipsychotics may mask, and therefore appear to improve, symptoms with treatment. Clinicians should attempt to avoid using typical antipsychotics in patients with preexisting abnormal movements. If abnormal movements again develop during treatment, clinicians should be aware that withdrawing the offending agent (especially if done too rapidly) could unmask and thereby worsen symptoms of TD. Patients at higher risk for TD are the elderly, women, those with prolonged treatment or past treatment with high doses of neuroleptics, those who developed significant parkinsonian side effects initially, and those with a history of affective disorders.
In contrast to other EPS, akathisia rates are generally similar among atypical antipsychotics, although there are lower overall rates with atypicals when compared with typical antipsychotics (10% to 20% vs. 20% to 50%, respectively).45 Identifying akathisia as the cause of agitation, restlessness, or even worsening psychosis or suicidality is crucial because treatment would include decreasing rather than increasing antipsychotic dose.
Restless Legs Syndrome
RLS has been reported with the use of antidepressants such as SSRIs,77 venlafaxine,78 and mirtazapine79 (as well as with several antipsychotics). Preliminary case reports suggest that bupropion, through modulation of dopaminergic effect, may be a better alternative antidepressant in patients with either preexisting or antidepressant-induced RLS.80
Women of Childbearing Age
Careful attention should be given to the choice of medication in young women. The general areas of concern are (a) the possibility of unplanned pregnancy while taking psychotropics and subsequent potential harm to the fetus (discussion of the care of the pregnant patient can be found in Chapter 14) and (b) the hormonal effects of medications on nonpregnant women.
Valproate may play a role in the development of polycystic ovary syndrome in women of reproductive age,81 thereby affecting fertility (although there is a lack of clarity regarding rates given a higher-than-baseline occurrence of polycystic ovaries in bipolar patients not taking valproate).82 In general, the use of mood stabilizers in young women can be very problematic given the possibility of interfering with fertility
(e.g., valproate), interacting to decrease effectiveness of oral contraceptives (e.g., carbamazepine), and then increasing the chances of congenital malformations (e.g., valproate, carbamazepine, and to a lesser extent lithium) should pregnancy ensue. Considering alternatives to treatment with mood stabilizers and providing patient education are particularly important when treating women of childbearing age.
(e.g., valproate), interacting to decrease effectiveness of oral contraceptives (e.g., carbamazepine), and then increasing the chances of congenital malformations (e.g., valproate, carbamazepine, and to a lesser extent lithium) should pregnancy ensue. Considering alternatives to treatment with mood stabilizers and providing patient education are particularly important when treating women of childbearing age.
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Psychiatric Education on the Inpatient Unit
Hospital Treatment of Depression and Mania
The Patient with Borderline Personality Disorder
Evaluation and Management of Substance Use Disorders on the Inpatient Psychiatric Unit
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