An approach to the psychopharmacologic care of patients: antidepressants, antipsychotics, anxiolytics, mood stabilizers, and natural remedies
An Approach to thePsychopharmacologicCare of Patients:Antidepressants,Antipsychotics,Anxiolytics, MoodStabilizers, andNatural Remedies
Jeff C. Huffman, , Jonathan E. Alpert, MD, PhD
Psychopharmacology Antidepressants Anxiolytics Mood stabilizers Antipsychotics Natural remedies
Dr Huffman has received research funding from the American Heart Association. Dr Alpert hasalso received research funding from the National Institute of Mental Health, National Alliancefor Research on Schizophrenia and Depression (NARSAD), Abbott Laboratories, Alkermes,Lichtwer Pharma GmbH, Lorex Pharmaceuticals; Aspect Medical Systems, Astra-Zeneca,Bristol-Myers Squibb Company, Cephalon, Cyberonics, Eli Lilly & Company, Forest Pharmaceuti-cals Inc., GlaxoSmithkline, J & J Pharmaceuticals, Novartis, Organon Inc., PamLab, LLC, PfizerInc., Pharmavite, Roche, Sanofi/Synthelabo, Solvay Pharmaceuticals, Inc., and Wyeth-AyerstLaboratories; has participated on advisory boards for or provided consultancy to Eli Lilly &Company, Pamlab LLC, and Pharmavite LLC; and has received speakers’ honoraria from Eli Lilly &Company, Xian-Janssen, Organon, Belvoir Media Group, and Informa Healthcare Publisher.
Drs Huffman and Alpert have received honoraria from Reed Medical Education for activitiesperformed for the MGH Psychiatry Academy.
a Harvard Medical School, 260 Longwood Avenue, Boston, MA 20115, USAb Department of Psychiatry, Massachusetts General Hospital, 15 Parkman Street, Boston,MA 02114, USAc Depression Clinical and Research Program, Massachusetts General Hospital, 50 StanifordStreet, Boston, MA 02114, USA* Corresponding author. Department of Psychiatry, Massachusetts General Hospital, 55 FruitStreet/Blake 11, Boston, MA 02114.
Med Clin N Am 94 (2010) 1141–1160doi:10.1016/j.mcna.2010.08.009
0025-7125/10/$ – see front matter Ó 2010 Elsevier Inc. All rights reserved.
The number of safe and effective medication treatments for psychiatric illness hasexpanded substantially over the past 10 to 15 years. Knowing when and how toprescribe psychotropics—and knowing which medication to prescribe—can be chal-lenging, but with knowledge of some basic principles, this task can be performedadeptly by physicians of all specialties. In this article, the authors discuss basic prin-ciples of psychopharmacology and outline an approach to using several commonlyprescribed classes of medications.
PRINCIPLES OF PSYCHOPHARMACOLOGYDeciding to Initiate Treatment
Optimal pharmacologic treatment depends on a good working diagnosis. The use ofan antidepressant alone for a college student who presents with depressed mood maybe appropriate if the diagnosis is of a major depressive episode, is likely to be insuf-ficient if the student is struggling with alcohol dependence or demoralized because ofproblems arising from an unaddressed learning disability, and is seriously inadequate(and possibly harmful) if the diagnosis is bipolar disorder or psychotic depression. Inacute situations, it may not possible to defer pharmacotherapy until a diagnosis is fullyclarified. In such situations, it is particularly important to document the differentialdiagnosis and the rationale for selecting a particular treatment and to specify the infor-mation needed to achieve greater diagnostic certainty, such as laboratory test resultsor information from collateral sources. In most circumstances, optimal care of patientswith chronic or complex psychiatric syndromes involves consideration of nonmedica-tion treatments in addition to, and sometimes instead of, pharmacologic approaches.
These range from an increasingly wide array of evidence-based psychosocial treat-ments (eg, cognitive-behavior therapy [CBT]), lifestyle interventions (eg, improvedsleep hygiene), and somatic treatments, such as electroconvulsive therapy (ECT).
Beyond clarifying the diagnosis, it is important to identify key target symptoms andgoals of treatment. If treating depression, for example, the clinician should identifythe symptoms that cause the most distress and that impair function, such as anhe-donia, suicidal feelings, or neurovegetative symptoms (eg, fatigue, impaired concen-tration, or insomnia). The clinician should also elicit examples of how the symptomsare impacting quality of life and function so that the patient and clinician can seriallyassess the impact of treatment on these important domains.
Once a decision is made to use a pharmacologic approach, a specific treatmentshould be chosen. In many cases (eg, with antidepressants), there are multiple agentswith essentially equivalent efficacy and safety. Research efforts are underway, partic-ularly in genetics, neurophysiology, and brain imaging, to identify clinically valid andreliable predictors of response that may guide medication selection in the future.
However, clinically useful biologic predictors are still lacking. An individual agent isusually chosen based on prior treatment responses, anticipated side effects, easeof dosing/monitoring, drug-drug interactions, comorbid conditions (eg, neuropathicpain, obesity) that could be affected positively or adversely, and cost. When initiatingtreatment, it is important to discuss certain aspects with the patient: the indication fortreatment, the time when benefits are anticipated, the potential side effects/risks andtheir expected time course and reversibility, the laboratory monitoring required whererelevant, the likely duration of treatment, the importance of regularly taking medication
(whether symptoms are reduced or not), and the existence of back-up possibilities iftreatment does not work (eg, other medications, psychotherapies, and nonpharmaco-logic somatic treatments, such as ECT). The understanding and beliefs of patients andthose close to them about psychotropic medications and the illness being treatedoften have a major impact on treatment adherence. Time taken at the outset to explainthe rationale for treatment and to address questions represents time well spent.
Follow-up visits should feature efficient, systematic inquiry about key target symp-toms/domains identified as relevant to the goals of treatment, safety (danger to selfor others), side effects and overall tolerability of treatment, medication adherence,as well as any salient changes to general health status, psychosocial status, anduse of prescription medication and over-the-counter (OTC) medications and supple-ments. Specific questions about common side effects (eg, sexual dysfunction ornausea) generally yield more useful information than open-ended inquiries. Likewise,nonjudgmental questions about impediments to adherence allow for more candiddiscussion than questions that tend to assume adherence (eg,“You’re taking themedicine 3 times a day as we discussed, right?”). To determine the efficacy of a courseof treatment, it is essential to aim for adequate trials in terms of duration and dose.
Steady dose titration as tolerated, ongoing encouragement of adherence, and willing-ness to discuss and address side effects are often key components to achieve thisgoal.
When discussing discontinuation of treatment with a patient, the risks of stoppingmedication must be discussed, especially the risk of relapse once off the medicationand the plan for monitoring for that risk. The method of discontinuation must also becarefully considered, because some psychotropic medications are associated withwithdrawal or “discontinuation emergent” symptoms on sudden cessation, andeven without a medication-specific withdrawal syndrome, relapse rates may be higherif treatment is abruptly stopped.These associated risks of discontinuing treatmentmust be weighed against the benefits (eg, reducing side-effect burden, potential druginteractions, cost, inconvenience).
Several factors may play a role in treatment failure.
The patient’s diagnosis
may be incorrect, or there may be critical comorbid condi-
tions (eg, substance use disorders) that may prevent resolution of symptoms (or effi-cacy of medication). The dose
of the medication may be suboptimal because ofinadequate dosing, problems with adherence, or pharmacokinetic issues (eg, concur-rent use of metabolic inducers, such as carbamazepine). Drugs
, both prescribed andillicit, can affect ongoing symptoms (eg, effects of steroids, such as prednisone, onmood) or influence drug levels (eg, effects of thiazide diuretics or high-dose nonste-roidal anti-inflammatory agents [NSAIDs] on lithium levels). Finally, disruptions
—psychosocial stressors—may also be potential impediments to treatment and shouldbe met with aggressive efforts to ensure the adequacy of pharmacologic treatmentand with equally determined efforts to develop a plan for addressing the environmentalfactors that seem to be compromising a patient’s recovery.
There are several commonly used classes of antidepressants. These include theselective serotonin reuptake inhibitors (SSRIs), the serotonin and norepinephrine reup-take inhibitors (SNRIs), and the atypical antidepressants (eg, bupropion and mirtaza-pine); summarizes indications, dosing, and side effects of these treatments.
Older classes of antidepressants (tricyclic antidepressants [TCAs] and monoamineoxidase inhibitors [MAOIs]) are still used occasionally. Overall, most of the evidencesuggests that these agents are roughly equivalent in the treatment of depression,and therefore, agent selection is often based on comorbid conditions, side-effectprofiles, treatment history, and cost.
The SSRIs are the most commonly prescribed antidepressants. All SSRIs share similarpharmacologic actions, including minimal anticholinergic, antihistaminic, anda1-adrenergic blocking effects, and potent presynaptic inhibition of serotonin reup-take. They are generally well-tolerated and are not as dangerous in overdose as arethe older agents, and many are available generically. The starting dose can serve asan initial target dose, and SSRIs are generally taken once daily. Another advantageis that they are effective for major depression, dysthymia, and nearly every anxietydisorder, including generalized anxiety disorder (GAD), post-traumatic stress disorder(PTSD), obsessive-compulsive disorder (OCD), and panic disorder (PD). Only minordifferences exist among the specific agents: citalopram, escitalopram, and sertralinehave the lowest risk of drug-drug interactions; whereas paroxetine is more oftensedating and has more anticholinergic effects; paroxetine and fluoxetine are potentinhibitors of cytochrome P450 2D6, requiring caution when coprescribing with certainsubstrates (eg, antiarrhythmics, lipophilic b-blockers, and TCAs); and fluvoxamineinhibits cytochrome P450 1A2 and 3A4, requiring caution when coprescribing witha range of medications (including theophylline, cyclosporine, midazolam, calciumchannel-blockers, and pimozide). When stopped abruptly, SSRIs can be associatedwith a discontinuation syndrome, with associated influenza-like symptoms (dizziness,nausea, headache), parasthesias, and sleep The syndrome is uncom-fortable but not dangerous and is most common with SSRIs having the shortesthalf-life (paroxetine and fluvoxamine); it is exceedingly rare with fluoxetine, whichhas a long-acting metabolite. Finally, use of SSRIs in pregnant women must be care-fully considered; these agents may be associated with some neurobehavioral distur-bances in the postpartum period (and paroxetine with persistent pulmonaryhypertension of the but untreated depression—and discontinuation ofeffective treatment—are also associated with poor maternal and neonatal outcomes.
Blocking the reuptake of serotonin and norepinephrine, the two most commonly usedSNRIs, venlafaxine and duloxetine, have been joined by desvenlafaxine, a metaboliteof venlafaxine more recently approved for treatment of major depressive disorder. Likethe SSRIs, these agents are generally well-tolerated and safer than older agents inoverdose; venlafaxine is available generically. SNRIs are effective for depressionand some anxiety disorders (eg, venlafaxine in GAD), although they have beenmuch less well-studied than SSRIs for anxiety disorders. Venlafaxine and probablydesvenlafaxine and duloxetine are associated with dose-dependent increases inblood pressureall three are associated with a discontinuation syndrome. Dulox-etine, like paroxetine and fluoxetine, is an inhibitor of cytochrome P450 2D6. SNRIs are
Nausea, anxiety, tremor, sedation, insomnia,
Low risk of discontinuation syndrome; cytochrome
Same as previous; possibly higher rates of
Short half-life; higher risk of discontinuation
syndrome; cytochrome P450 1A2 and 3A4 inhibition
Same as previous; possibly higher rates of
Short half-life; higher risk of discontinuation syndrome;
sedation; mild anticholinergic side effects
Same as previous; possibly higher rates of
Few drug-drug interactions; moderate cytochrome
Probable dose-dependent increase in blood pressure;
probable association with discontinuation syndrome
Associated with rare increase in liver function tests;
Dose-dependent increase in blood pressure can occur;
high rates of discontinuation syndrome if stoppedabruptly
Headache, insomnia, tremor, anxiety; lower
Increased risk of seizure at doses>450 mg/d;
Sedation, increased appetite, weight gain,
Can be associated with increases in lipids
not well-studied in pregnant patients and should be used with caution. Dual reuptakeinhibitors, like the older TCAs, such as amitriptyline, but unlike the SSRIs, seem tohave a role in the treatment of pain syndromes, particularly neuropathic pain, andare therefore often considered for treatment of depressed patients with comorbidpain.
Mirtazapine, a serotonin-receptor blocker that also has effects on norepinephrine viablockade of a2-adrenergic receptors, and bupropion, an agent with effects on norepi-nephrine and dopamine, represent important alternatives to the SSRIs and SNRIs and,for treatment-resistant depression, are sometimes used in combination with them inmore complex pharmacologic regimens. Both are used primarily for the treatmentof depression, evidence for their efficacy in anxiety disorders being sparse; bupropionhas been found to be effective as an agent for smoking cessation and also is partic-ularly unlikely to cause sexual dysfunction. However, bupropion, like some of theSSRIs and SNRIs, is a potent inhibitor of cytochrome P450 2D6. Mirtazapine causessignificant blockade at histamine (H1) receptors and 5-HT2 receptors, leading to seda-tion and increased appetite/weight gain; this may be problematic for many patientsbut it can be beneficial for patients who sleep and eat poorly. Bupropion, in contrast,is not associated with sedation or weight gain but may be associated with insomnia,jitteriness, or anxiety. Both agents are relatively safe in overdose, although bupropionhas also been associated with an increased risk of seizures at higher than recommen-ded doses (single doses higher than 150 mg of the immediate-release formulation,200 mg of the sustained-release formulation, or higher than 450 mg/d), and seizureis a risk with bupropion overdose as well as in patients at risk of seizure, such as thosewith a central nervous system lesion or active eating disorder. Neither agent is well-studied in pregnancy.
These older agents are limited by their greater risk in overdose, potential effects oncardiac conduction/arrhythmias (TCAs), and substantial required restrictions on dietand medications (MAOIs). TCAs are also associated with orthostatic hypotension,sedation, and anticholinergic effects, and MAOIs commonly cause orthostasis aswell. TCAs are still sometimes used at low doses for sleep or neuropathic pain, andan MAOI (selegeline) patch has been developed that does not require dietary restric-tion at the lowest available dose, although restrictions on several drug classes are stillrequired, even at the lowest dose.
Practical approaches to treatmentFor many patients, including those with anxiety disorders (in isolation or with comorbiddepression), SSRIs are a natural first-line choice among antidepressants. There are,however, specific situations in which using a different class of agent may make sense(eg, patients who are trying to quit smoking or have had problems with sexual dysfunc-tion on serotonergic agents [bupropion], patients who have very poor appetite andsleep [mirtazapine], or patients with comorbid neuropathic pain [duloxetine]). Whenprescribing antidepressants, the lowest usual therapeutic dose is customarily consid-ered (eg, citalopram 20 mg), but if there is less than 20% to 30% improvement over theensuing 2 to 4 weeks and adequate tolerability, the dose should be pushed upward. Ifa depressed patient has a minimal response to an adequately and aggressively dosedtrial of an SSRI or is unable to tolerate the medication, switching to a second SSRI oranother class of agent (eg, SNRI or bupropion) seems to be equally effective.If the
patient has a partial response to the maximally tolerated dose of an SSRI, rather thanswitching agents, many clinicians choose to continue the SSRI and add a second anti-depressant, usually bupropion or mirtazapine, or consider adding a nonantidepressantwith evidence for efficacy as augmentation of antidepressants. Various nonantide-pressant agents have been used as augmenting agents (including lithium, triiodothy-ronine [T3] dopamine agonists, such as pramipexole, buspirone, the antianxiety agent,and psychostimulants, such as methylphenidate) with varying degrees of evidence.
However, in recent years, the atypical antipsychotics (eg, aripiprazole, quetiapine,olanzapine) have received particularly active attention as well as Food and DrugAdministration-approval for antidepressant augmentation. Nevertheless, their risks,particularly of metabolic syndrome and extrapyramidal side effects, and their costsmust be considered in each case.
ANXIOLYTICS AND SLEEP AGENTSBenzodiazepines
The most commonly used antianxiety agents are benzodiazepines areagonists at specific g-aminobutyric acid (GABA)A receptors and are used for varioussymptoms and syndromes that include free-floating anxiety, PD, insomnia, andmuscle spasm. Benzodiazepines have the advantage of being rapidly effective buthave several caveats associated with their use. They have been associated withincreased risk of falls, development of delirium (especially in persons with pre-existingcognitive disorders), and potential for respiratory depression.Furthermore, long-term use of these agents leads to physiologic dependence, and if and when discon-tinued, they require tapering off. Because of these disadvantages, the SSRIs andSNRIs have become the mainstay of longer-term treatment of many anxiety disorders(including PD, GAD, social anxiety, OCD, and PTSD). Because of the potential fordeveloping dependence, benzodiazepine use for patients with prior or ongoingsubstance-use disorders must be considered carefully. However, when these agentsare used at appropriate doses for appropriate indications (eg, PD), they are effective,and dose escalation does not typically occur.Selection of a specific benzodiazepinedepends on several factors. For example, diazepam and clonazepam have longer half-lives, allowing less frequent dosing and less fluctuation of blood levels; these agentsare widely used for patients who need standing treatment throughout the day (eg, PD).
In contrast, lorazepam and oxazepam are shorter-acting and may be more beneficialwhen used as-needed for insomnia or for patients with impaired hepatic metabolism.
These agents have been used effectively in pregnant women, although they may beassociated with low birth weight and neonatal sedation in the
The agents zolpidem, zaleplon, and eszopiclone are short-acting agents used specif-ically for insomnia. These sedative-hypnotics are GABAA receptor agonists but do notact on the benzodiazepine receptor per se and have shorter half-lives than mostbenzodiazepines. These agents are effective in the treatment of insomnia and areusually well-tolerated. Although they have less risk of physiologic dependence thanbenzodiazepines, at high doses, dependence and a withdrawal syndrome canoccur.One set of potentially adverse effects associated with these medications isrelated to nocturnal behaviors; a small subset of patients taking these medicationsengage in sleepwalking, nighttime eating, or more complex behaviors that occurduring sleep; the patient is typically amnestic for these events.This syndrome
metabolism; better choicein patients with hepaticinsufficiency
has most frequently been observed with the use of zolpidem. Although rare, it is impor-tant to warn patients of these potential effects.
Trazodone is an antagonist at serotonin and a-1 receptors. It was initially marketed asan antidepressant but is now more frequently used to treat insomnia. It is generallyeffective and well-tolerated, although it can cause daytime sedation, orthostatic hypo-tension, and, very rarely, priapism in men. Ramelteon is a sleep agent with a differentmechanism—it is a melatonin-receptor agonist, and it may be helpful with insomnia orshifted sleep-wake cycles. Overall, ramelteon is quite well-tolerated but, clinically,tends to be less effective in actively inducing sleep than other agents.Finally, bus-pirone is an agent that was developed for the treatment of GAD; it has the advantageof being very well-tolerated and having no risk of physiologic dependence. However,although it has been used for GAD and as an adjunct to antidepressant treatment ofdepression, some clinicians find that it has limited effectiveness, particularly forpatients who have been treated previously with benzodiazepines.
Practical approach to treatmentWith respect to the pharmacologic treatment of anxiety, assessing the nature of theanxiety before embarking on treatment is critical. Specifically, does the patient havea formal anxiety disorder (eg, GAD or PD) or simply periods of anxiety? Brief situationalanxiety or certain phobias (eg, flying) can be reasonably well treated with a brief courseof benzodiazepines, often at low doses, although behavioral approaches are highlyeffective and should be considered for patients with recurrent difficulty with situationalanxiety or simple phobias. Panic disorder is often rapidly responsive to moderate-to-high–dose benzodiazepines, such as clonazepam (which may be used on a standingbasis), although is also treated over the longer-term with SSRIs because of the poten-tial risks associated with chronic benzodiazepine use. On the other hand, other anxietydisorders (eg, OCD, GAD, PTSD) are often better treated primarily with SSRIs (orSNRIs), sometimes with benzodiazepines for augmentation. With insomnia treatment,it is likewise helpful to determine if the insomnia occurs in the context of anotherpsychiatric illness (eg, depression) or a medical disorder (eg, restless legs syndromeor obstructive sleep apnea) to determine if targeted treatment of the underlying illnessis needed. Polysomnography should be considered for persistent sleep disturbance ofunclear cause. If insomnia is the primary problem and sleep hygiene techniques do nothelp, first-line options include the use of short-acting GABA agents, like zolpidem(which have lesser impact on rapid eye movement (REM) sleep than other agentsand do not tend to cause oversedation) or trazodone (which may impact REM sleepmore and is longer-acting but is not associated with nighttime behaviors).Althoughshort-term treatment of insomnia is ideal, some patients, particularly those withcomorbid psychiatric and medical conditions (eg, chronic pain) that may cause persis-tent challenges to sleep, seem to require maintenance standing sleep medicationusing the lowest effective dose of sedative-hypnotic and ongoing monitoring to reas-sess risks and benefits.
Among the mood stabilizers—agents used to prevent or treat manic or depressiveepisodes among patients with bipolar disorder—lithium has been used the longestand, in some ways, remains the gold standard of this class, particularly for classic
bipolar disorder characterized by distinct episodes of full mania and depression
(The mechanism by which lithium and the other mood stabilizers workremains unclear and may be the result of effects on neurotransmitters or other,more upstream effects (eg, on gene expression). Lithium can be used to treat themanic and depressive phases of illness, and as a maintenance agent, it has beenshown to reduce the risk of suicide.However, initiation and continuation of lithiummust be considered and monitored carefully, given that this agent is also associatedwith multiple side effects, has a narrow therapeutic index, and is involved in multipleclinically significant drug-drug interactions. In addition to more common side effects(eg, tremor, weight gain, cognitive dulling, and polydipsia/polyuria), lithium is alsoassociated with the development of hypothyroidism and with the gradual develop-ment of renal insufficiency/failure. At levels higher than the therapeutic range (gener-ally considered to be 0.6–1 mEq/L), toxicity can begin, with the onset of symptomstypically around 1.5 mEq/L and more serious symptoms, including stupor, dysarthria,severe tremor, ataxia, and delirium, at higher levels. Given these risks, it is important tofollow lithium levels (especially during initiation and dose changes) and to systemati-cally monitor renal function every 3 to 6 months. Also, several commonly prescribedmedications, including prescription-strength NSAIDs, angiotensin-converting enzymeinhibitors, and thiazide diuretics, can increase lithium levels and lead to toxicity,whereas aminophylline and theophylline may cause lithium levels to decrease. Useof lithium during pregnancy is associated with an elevated risk of Ebstein ;however, it otherwise does not appear to be associated with major malformations andis generally considered to be the treatment of choice among pregnant women withbipolar disorder, although levels need to be monitored closely because of fluid/volumeshifts during the course of pregnancy.
Valproic acid is the anticonvulsant for which there is the most evidence of efficacy inbipolar disorder, especially for the treatment of acute manic episodes and as mainte-nance treatment to reduce risk of relapse into mania or depression. It is sometimesused more generally for the treatment of impulsivity and aggression. Valproic acidcan be titrated much more aggressively than lithium for manic patients, has a muchwider therapeutic index, and is less dangerous in toxicity/overdose. However, it stillcan have side effects—sedation, weight gain, gastrointestinal (GI) upset, and diarrheaare among the most common—and can less commonly be associated with elevationsin liver function tests and with platelet dysfunction. Hyperammonemia or pancreatitismay present emergently though rarely on valproic acid use. With regard to drug-druginteractions, it can slow the metabolism of aspirin, warfarin, lamotrigine, and somebenzodiazepines (eg, diazepam), increasing levels of those medications. Valproicacid has been strongly associated with neural tube defects and generally should beavoided in pregnant women.
Lamotrigine is effective in the treatment of bipolar depression and in preventing
recurrent mood episodes, especially depression. It is well-tolerated, does not havesignificant associated weight gain, sedation, or GI side effects, and does not requiremonitoring with laboratory tests. However, rapid titration of lamotrigine is associatedwith dangerous dermatologic conditions, including Stevens-Johnson syndrome, andtherefore, the dose must be slowly increased over the course of many weeks; patientsshould be told to contact their physician with any rash associated with lamotrigine use.
Concomitant use of valproic acid, which is common in the management of patientswith refractory bipolar states, requires a slower rate of lamotrigine titration to avoidthis risk. Based on limited available information, use of lamotrigine in pregnant womenseems to be associated with elevated rates of oral
Table 3Lithium and selected anticonvulsant mood stabilizers
Abbreviations: ACE, angiotensin-converting enzyme; A-II, angiotensin-II; BUN, blood urea nitrogen; CBC, complete blood count; GI, gastrointestinal; LFTs, liverfunction tests; TSH, thyrotropin.
Carbamazepine and the related compound oxcarbazepine have also been used in
the treatment of patients with bipolar disorder; they (particularly oxcarbazepine) maybe less effective than valproic acid for manic symptoms and less effective than lamo-trigine for depression. One advantage of these agents is that they are not—in contrastto most other mood stabilizers—associated with significant weight gain. Both agentsare associated with hyponatremia; carbamazepine, and, to a lesser degree, oxcarba-zepine, can induce the metabolism of medications, especially those metabolized bythe 3A4 isoenzyme of the cytochrome P450 system (eg, immunosuppressants,protease inhibitors, and oral contraceptives [OCPs]). Indeed, both agents can inducethe metabolism of OCPs, and patients should be told to use another form of contra-ception, especially given the risk of neural tube defects associated with carbamaze-pine and possibly oxcarbazepine. Carbamazepine has also been associated withaplastic anemia and dermatologic side effects, including development of Stevens-Johnson syndrome. Finally, other anticonvulsants (eg, topiramate, gabapentin)seem to be less effective as mood stabilizers than those listed earlier, and their rolein bipolar disorder is generally reserved for targeting other co-occurring conditionsfor which they may be effective.
Practical approach to the use of mood stabilizersIn addition to lithium and the anticonvulsants discussed earlier, several atypical anti-psychotics have been shown to be effective in the management of mood episodes inbipolar disorder, even in the absence of psychotic symptoms. Although these agentshave a much less narrow therapeutic index than lithium or carbamazepine and do notrequire therapeutic-level monitoring, they do entail risk of metabolic syndrome, whichrequires ongoing monitoring, and there is a risk of extrapyramidal symptoms (EPSs).
Overall, when selecting a specific pharmacologic agent to treat a patient with bipolardisorder, it is often helpful to consider the patient’s current clinical state. For acutemania
, valproic acid and atypical antipsychotics can be titrated upward most rapidlyand are often considered to be first-line agents; lithium can also be used, but it is typi-cally paired with a second agent that can be used to quell symptoms while lithium isbeing more gradually titrated upward. For patients with acute bipolar depression
,lithium, lamotrigine, and quetiapine, the atypical antipsychotic, are often consideredto be first-line agents. Finally, for patients who are currently stable but who requiremaintenance treatment of bipolar disorder, lithium is the treatment of choice for thosewho can safely take this medication; valproic acid and several atypical antipsychotics(eg, olanzapine or aripiprazole) are also reasonable options. Given the significantshort- and long-term side effects that can be associated with all these medicationsand the need for laboratory monitoring with many of them, the patient and clinicianshould carefully consider the risks, benefits, and potential side effects of the reason-able available options and come to a collaborative decision. Although antidepressantsare not infrequently used for bipolar depression, their efficacy in bipolar disorderremains uncertain, and their use is thought to increase the risk of mania, rapid cycling,or mixed manic/depressive states for some patients. Antidepressants should gener-ally be used sparingly in the treatment of patients with bipolar disorder and only inthe setting of adequate mood stabilization with other agents.
This older class of antipsychotic agents, which include haloperidol, fluphenazine, andperphenazine, work by blocking dopamine D2 receptors (Currently, thesemedications are used much less frequently than the newer atypical antipsychotics.
Abbreviations: Ach, anticholinergic; EPS, extrapyramidal symptoms; PRL, prolactin; TD, tardive dyskinesia.
a When used for schizophrenia spectrum disorders; doses may differ for other indications.
b New agent; limited clinical data regarding side effects is available.
The typical antipsychotics are used primarily for the treatment of schizophrenia spec-trum disorders; however, they can be used to treat patients with psychotic symptomsassociated with other syndromes, including psychotic depression (in combination withan antidepressant), mania with psychotic features, and delirium. They have fallensomewhat out of favor because of side effects that can include EPSs (dystonia,parkinsonism, and akathisia) and tardive dyskinesia (TD; a long-term, relatively irre-versible side effect causing involuntary motor movements) and, rarely, neurolepticmalignant syndrome. However, these medications are very effective in the treatmentof psychosis, and large studies have found that they may be as effective as the atyp-ical antipsychotics in the treatment of Furthermore, they can usuallybe dosed once daily, and particularly the higher-potency agents (eg, haloperidol)seem to have lesser metabolic side effects than some of the atypical antipsychotics.
There is more evidence for their relative safety in pregnancy than the atypical antipsy-chotics.Particularly at high doses, there is a risk of arrhythmia accompanying use ofthe low-potency agents (eg, chlorpromazine, thioridazine) and some of the otheragents (eg, pimozide and intravenous haloperidol or droperidol).
This class of antipsychotics is differentiated from the typical ones by their blockade ofserotonin 5-HT2A receptors and by lack of a linear relationship between clinicalpotency and D2-receptor blockade; some agents (eg, risperidone) have substantialeffects on D2 receptors, whereas others (eg, quetiapine) having almost none, althoughacting on other dopamine receptors. The atypical antipsychotic aripiprazole, ratherthan blocking dopamine receptors, is a partial dopamine receptor agonist. Overall,atypical antipsychotics are effective for all conditions treated by typical antipsy-chotics, and many seem to be effective in patients with bipolar disorder for acutemania and as maintenance mood stabilizers. These agents vary in their side effectsbut, overall, have a lower risk of TD compared with the typical antipsychotics and,in general, are rather well-tolerated. Metabolic side effects, however, have becomea major concern with some of these agents, with associations between the agentsand the development of metabolic syndrome (including weight gain, hyperlipidemia,and development of diabetes). Metabolic side effects seem to be greatest with cloza-pine and olanzapine, intermediate with risperidone/paliperidone and quetiapine, andrelatively minimal with ziprasidone and aripiprazole.Given these concerns, patientstaking atypical antipsychotics should have regular monitoring of weight, blood pres-sure, lipids, and blood glucose.Clozapine, because of its potential to cause agran-ulocytosis in up to 1% of patients, has restrictive prescribing and monitoringrequirements, such that patients must have their white blood cell count measuredweekly for the first 5 months and every other week for the remainder of treatment.
These agents are not yet well-studied in pregnancy, and the older typical agents aregenerally used to treat and prevent psychotic symptoms in pregnancy.
Two antipsychotics have recently been introduced in the United States. Iloperi-
done blocks serotonin 5-HT2A receptors and, to a lesser degree, D2 receptors; phar-macologically, it seems somewhat similar to risperidone, although it seems to beassociated with fewer EPSs; orthostasis with initial use requires slow titration of ilo-peridone to the target dose. Asenapine works via blockade of multiple serotonin anddopamine receptors; it seems to have potentially lower risk of weight gain than mostatypical antipsychotics, although associated with akathisia and other EPSs. The rela-tive benefits of these agents compared with other atypical antipsychotics are yet tobe determined.
Practical approach to the use of antipsychoticsIn general, most antipsychotics are equally effective in the treatment of psychoticdisorders, and therefore, decision-making about specific medications revolves aroundside effects, long-term effects, cost, and other practical issues. Also, a limited subsetof antipsychotics are available for intravenous administration, particularly helpful inintensive care unit settings; others are available in long-acting injectable depot formfor longer-term use as noted in later discussion. When possible, the pros and consof several agents should be discussed with patients and their families. When dosingwith these agents, it is important to maintain a balance: one must allow time for thesemedications to have an effect (especially when dealing with long-held delusionalbeliefs and/or chronic schizophrenia spectral illness, which can take quite sometime to respond); it is also important to ensure that a systematic up-titration of doseis undertaken if symptoms are not fully responding to the current dose. The frequencyand rate of dose increase depends on the severity and acuity of psychotic symp-toms—possibly every few days. more often for a patient with acute psychotic symp-toms necessitating psychiatric admission, or monthly for patients with chronicsymptoms that do not profoundly impact function.
Long-acting injectable forms of antipsychotics (eg, long-acting haloperidol, fluphen-
azine, risperidone, paliperidone, and olanzapine) should be considered fairly early inthe course of treatment to avoid unnecessary morbidity and, ideally, to improve thecourse of illness for patients experiencing serious relapses related to recurrentnoncompliance with medication; this is a not infrequent challenge, often linked topoor insight inherent in psychotic illness. For patients who do not respond to adequatetrials of multiple antipsychotics, clozapine does, in fact, seem to be more effectivethan the other agents for refractory psychotic disorders and some severe mood disor-ders, and it should be considered in such patients; however, its multiple serious sideeffects, risks of seizure and agranulocytosis, and need for ongoing hematologicalmonitoring generally relegate it to being used only for these refractory cases.
Several preparations of natural remedies, available OTC as dietary health supple-ments without formal illness indication, have been formally studied to assess theirimpact on psychiatric conditions In many cases, the studies have not foundthese treatments to be greatly effective, but these agents may help some patients withmood symptoms, anxiety, and insomnia, particularly those who are reluctant to takeprescription medications, have not responded to or tolerated adequate trials ofbetter-established agents previously, or wish to cautiously augment their regimenswith these other agents. Given their popularity and widespread use among patientswith psychiatric conditions, it is crucial for clinicians to ask patients whether theyare taking OTC supplements because of their potential interactions with prescribedmedications.
Natural agents used for depression include S-adenosylmethionine (SAMe), Omega-3fatty acids, and St John’s wort. SAMe is involved in the methylation of neurotransmit-ters, nucleic acids, proteins, and phospholipids; its role in the production of serotonin,norepinephrine, and dopamine may best explain SAMe’s putative antidepressantproperties.Several meta-analyses have found SAMe to be more effective thanplacebo in the treatment of unipolar depression, although at generally high doses.SAMe is generally well-tolerated; however, serotonin syndrome (SS), characterized
Table 5Selected natural remedies used to treat psychiatric symptoms
antidepressants or other serotonergicdrugs
Reduced levels of certain critical drugs,
such as immunosuppressants, warfarin,antiretrovirals, and digoxin. Alsopossible SS with serotonergic drugs
that also have effects at GABAreceptors (eg, benzodiazepines)
Abbreviations: DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; SAMe, S-adenosylmethionine; SS, serotonin syndrome.
by confusion, fever, myoclonus, and hyperreflexia, may be a risk when SAMe iscombined with highly serotonergic agents. Nevertheless, several small trials havebeen undertaken in which SAMe has been used to safely augment SSRIs and SNRIs.
Omega-3 fatty acids, which may work by affecting neurotransmitter signaling, regu-lating calcium channels, lowering plasma norepinephrine, or inhibiting secretion ofinflammatory cytokines, have been studied for patients with both unipolar and bipolardepression, with generally positive but somewhat mixed results. At this stage, it isgenerally thought that the best evidence points to use of these agents to augmentstandard treatments rather than to be used as montotherapy.St John’s wort maywork by the inhibition of cytokines, a decrease in serotonin receptor density,a decrease in reuptake of neurotransmitters, and weak MAOI Overall,St John’s wort seems to be effective for milder forms of depression but may be lesseffective than standard agents in the treatment of more serious Initialconcerns about the risk of SS when combined with serotonergic agents have onlybeen weakly borne out. However, case reports and clinical trials indicate that somecritical medications may be rendered less effective in some patients concurrentlytaking
(eg, cyclosporine and tacrolimus), warfarin, antiretrovirals, digoxin, and oralcontraceptives.
Agents used for Anxiety, Sleep, and Memory
Kava is a natural remedy for anxiety; its mechanism may be attributable to kavapyr-ones, which are central muscle relaxants that are thought to be involved in blockadeof voltage-gated sodium ion channels, enhanced binding to GABAA receptors, dimin-ished excitatory neurotransmitter release, and reduced reuptake of norepinephrine.
Kava’s use has been much reduced over the last several years because of concernsthat it may lead to hepatotoxicity.Melatonin is a hormone made in the pineal glandthat has been shown to help travelers avoid jet lag and to decrease sleep latency forthose suffering from insomnia; it may also help night-shift workers maintain regularsleep-wake cycles. Melatonin is derived from serotonin and is thought to play a rolein the organization of circadian rhythms. Finally, Ginkgo biloba
is a natural remedymade from the seed of the Ginkgo tree that has been used to address cognitive impair-ment and enhance memory; it may work via neuronal stimulation/protection and scav-enging of free radicals. Although some studies have found benefit for these agents inmodestly improving memory in demented and nondemented patients, overall, theevidence for such benefit remains mixed.Ginkgo has been associated with anincreased risk of bleeding; therefore, it should be used with caution in patients atrisk of bleeding or those taking anticoagulant medications.
Practical approach to natural remediesThe most important thing regarding natural remedies is for clinicians to regularly askpatients about their use and to be aware of their potential interactions with prescribedmedications, psychiatric and nonpsychiatric. Also, as federal regulation of dietaryhealth supplements differs markedly from that of prescription medications, it is helpfulfor patients to know that marked differences in bioavailability may exist acrossdifferent brands and formulations of a given product. Nevertheless, inherent in thedoctor-patient relationship is a commitment to negotiating treatment decisions withthe patient in the context of available evidence about risks and benefits. In the settingof patient interest in discussing OTC remedies and other possible complementary andintegrative approaches, the willingness of a clinician to address their use thoughtfully,
albeit cautiously, and with acknowledgment of limited data and expertise, may rein-force a patient’s trust and treatment adherence.
A growing range of safe and effective pharmacologic treatments allows for increas-ingly targeted and resourceful care of patients with psychiatric conditions. In manycases, these treatments will be delivered alongside other care, including psychother-apies and lifestyle interventions as well as other medical care; this requires coordina-tion and good communication with the patient, significant others, where appropriate,and other clinicians. Optimal pharmacotherapy starts with articulation of a workingdiagnosis and of treatment goals and continues with a plan for ongoing, structuredmonitoring of symptoms, safety, side effects, adherence, and changes in generalhealth status and psychosocial status. Although progress is being made toward thedevelopment of clinically relevant biomarkers and other predictors of drug response,consideration of previous treatment responses, primary and comorbid conditions andsymptoms, side-effect profile, drug-drug interactions, and cost often help narrowavailable treatments to those best suited in a particular clinical context. Beyondselecting appropriate medications and a thoughtful plan for dose titration and moni-toring, ensuring that patients has a good understanding of the rationale and plan fortreatment and ample opportunity to have questions and concerns addressed at theearliest possible stage in treatment is crucial to medication adherence. For manypatients with psychiatric conditions, as with other chronic medical conditions, adher-ence involves a commitment measured not in days or weeks but in months and yearsand is core to the success of treatment.
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Director of Biostatistics (2004-2006), Omni Genetics (Menlo Park, CA). Omni Genetics seeks to discover connections between adverse response to pre-scription drugs and genetic variation potentially responsible. My role was aidingthe design and interpretation of experiments and clinical trials. As the biosta-tistician, I worked with the officers of the company and with our pharmaceuticaland biotech