Vol. 22, No. 04 / November 2010
Medical Management of Bipolar Disorder: A Pharmacologic PerspectiveMatthew A. Fuller, PharmD, BCPS, BCPP, FASHP
Clinical Pharmacy Specialist, Psychiatry, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Brecksville, Ohio, Clinical Associate Professor of Psychiatry, Clinical Instructor of Psychology, Case Western Reserve University, Cleveland, Ohio, Adjunct Associate Professor of Clinical Pharmacy, The University of Toledo, Toledo, Ohio
Mechanisms of Action of Major Classes of Medications Used to Treat Bipolar Disorder
Numerous medications are available to treat bipolar disorder (BD) I and II. These include mood stabilizers, antipsychotic agents, and antidepressants (Table 1).1-21 Understanding their respective pharmaco-logic and clinical profiles is critical to improved patient care. Here, we will explore select features of mood stabilizers and antipsychotics, while the next chapter will provide perspectives on use of antidepressants.
Approved Medications for Bipolar Disorder.1-5
FDA approved indication(s)
X (as adjunct)
Risperidone long-acting injection20
X (as adjunct)
BD I=bipolar I disorder; ER=extended release; FDA=Food and Drug Administration.
a Only Equetro® ER capsules approved for BD.
b Only Depakote® DR capsule, DR and ER tablets approved for manic episodes associated with BD.
Equetro is a registered trademark of Validus Pharmaceuticals.
Depakote is a registered trademark of Abbott Laboratories.
The pathophysiology of mood disorders is complex, and a focus on the correction of neurochemical deficits alone has proven simplistic.22,23 Recently, researchers have focused on how pharmacotherapeutic agents influence neuroplasticity.1,24,25 Conventional medications used for BD mediate their effects through complex biochemical cascades, as illustrated in the Figure.1 The various mood stabilizers available to clinicians—including lithium and anticonvulsants such as carbamazepine, valproic acid, and lamotrigine— operate through neural signaling pathways, the clinical implications of which are as yet unknown. Translational research efforts are underway to delineate precisely how mood stabilizing agents influence neurotransmitter receptors and their respective intracellular signaling pathways that affect gene expression, cell differentiation, proliferation and death, and the structure and function of nerve cell activity. Select agents have been linked directly with changes in gene expression and neuroplasticity.1 For example, lithium and valproic acid enhance expression of brain-derived neurotrophic factor (BDNF), activation of which inhibits programmed cell death, or apoptosis, and promotes cellular proliferation.1 These agents also inhibit glycogen synthase kinase-3 (GSK-3), a pro-apoptotic enzyme highly expressed in the hippocampal neurons and involved in synaptic plasticity.26 Inhibition of GSK-3, therefore, is thought to protect neurons from apoptosis.27-29 Mood stabilizers also increase expression of a critical antiapoptotic protein, Bcl-2.1 Precisely how these molecular and cellular events modulate mood, emotion, affect, and other clinical features we see in our patients remains only partly understood. Table 2 summarizes the mechanisms of action (MOA) of medications used for BD.1,3-5,30-38
Mechanism of Action of Medications Used to Treat Bipolar Disorder.
Decreases stimulation of neural discharge related to the influx of sodium ions across cellular membranes5,38; depresses neuronal activity in the nucleus ventralis of the thalamus4
Increases GABA activity and mimics the action of GABA at the postsynaptic receptor; enhances BDNF expression3,37; inhibits GSK-3; increases the antiapoptotic protein Bcl-236
Increases glutamate clearance and decreases glutamate release, protecting against damage to neurons and glia1; inhibits voltage-sensitive sodium channels that are thought to stabilize neuronal membranes35
Increases glutamate clearance and decreases glutamate release, protecting against damage to neurons and glia34; enhances BDNF expression33; inhibits GSK-331,32; increases the antiapoptotic protein Bcl-236
Act at serotonin, norepinephrine, and dopamine receptors on the cell surface to produce variable effects on signal transduction cascades, resulting in downstream changes in metabolism, energetics, and gene expression1,30
BDNF=brain-derived neurotrophic factor; GABA=gamma-aminobutyric acid; GSK-3=glycogen synthase kinase-3.
Antipsychotics include the typical agents (eg, haloperidol, chlorpromazine, fluphenazine, and perphenazine) and the following atypical agents approved for BD in the United States: aripiprazole, asenapine, olanzapine, quetiapine, risperidone, and ziprasidone. The atypical antipsychotic clozapine is not approved for BD, but this agent may be used for treatment-resistant individuals with BD.39-42 While the mechanisms underlying the efficacy of these agents in BD are not well understood, modulation of dopamine and serotonin levels is thought to be important in acute mania and maintenance treatment (Tables 1, 2). More specifically, some antipsychotics may affect the GSK-3 signaling pathway and regulate central responses to environmental stressors by inhibiting corticotropin-releasing hormone (CRH) secretion from the hypothalamus and the hippocampus.2,43 The selection of an antipsychotic agent for the management of BD should be determined after a thorough assessment of bipolar subtype (BD I vs BD II) and associated features (eg, psychosis, rapid cycling), prior treatment response, patient side effect experience, medication side effect profile, patient preference, adherence history, risk for drug-drug interaction, and cost.44
Typical and atypical antipsychotics vary widely in their affinity for dopaminergic, serotonergic, and other receptors (Table 3).45,46 In some cases, adverse event profiles are influenced positively (Table 4).47 For example, aripiprazole (currently indicated for schizophrenia and for acute and maintenance treatment of manic/mixed episodes associated with BD I) has no muscarinic activity and, thus, few anticholinergic side effects.13 Further, it does show partial agonist activity at dopamine D2 and 5-HT1A receptors, suggesting that it may be beneficial in the depressed phase of a mood disorder.48 Some evidence indicates that olanzapine has weak activity at gamma aminobutyric acid (GABA) and benzodiazepine receptors, implying that it may have a calming effect similar to that of an anxiolytic, and is also approved for acute and maintenance treatment of BD.49 Ziprasidone, a serotonin-dopamine antagonist, is also a partial 5-HT1A agonist, with putative anxiolytic actions.50 This agent also inhibits serotonin and norepinephrine reuptake and may show some efficacy as an antidepressant.51 An olanzapine-fluoxetine combination translates to a greater serotonergic effect and for this reason has been found useful in individuals with BD I depression.52 In addition, the olanzapinefluoxetine combination may be particularly beneficial in bipolar depression due to its synergistically therapeutic impact on serotonin, norepinephrine, and dopamine levels in the central nervous system (CNS). Other approved antipsychotics, such as chlorpromazine, asenapine, quetiapine, and risperi-done, are effective for the treatment of mania.53-56 Quetiapine may also be used to treat acute depression in both BD I and BD II.57,58 Further, quetiapine and risperidone long-acting injection are useful for maintenance therapy and monotherapy/adjunctive therapy, respectively.59,60
Most patients with BD require a combination therapy, as indicated by studies listed in Table 5.61-73 According to these and related data, combination therapies are more effective than monotherapy.72 The new emphasis is now on treating acute and maintenance phases to remission and attempting to maintain this in long-term prophylaxis because of the potentially devastating psychosocial, cognitive, and medical consequences of inadequately treated illness and repeated relapses. Minor symptom breakthroughs are also precursors of more major episode recurrence. Long-term careful monitoring is essential. Such a shift in emphasis to the long-term has important implications for the choice of agents not only regarding efficacy but especially long-term tolerability.
Receptor Binding Profiles of Antipsychotics.45,46,a
Dopamine D 2
Serotonin 5-HT 2A
Acetylcholine muscarinic M 1
Histaminic H 1
aData represented as the equilibrium constant (Ki) (nM), ie, nanomolar amount of the antipsychotic needed to block 50% of the receptors in vitro. Therefore, a lower number denotes stronger receptor affinity and binding; bData from cloned human brain receptors; cDopamine D2L; dPartial agonism.
Relationship Between Receptor Activity and Adverse Effects.47
α1 (adrenergic) antagonism
Postural hypotension; dizziness; reflex tachycardia; potentiation of antihypertensive effects of prazosin, terazosin, doxazosin, and labetalol
α2 (adrenergic) antagonism
Blockade of antihypertensive effects of clonidine, hydrochloride, guanabenz acetate, and methyldopa
D2 (dopamine) antagonism
EPS (Parkinsonism, dystonia, akathisia), tardive dyskinesia, endocrine effects due to hyperprolactinemia (eg, galactorrhea, gynecomastia, menstrual changes, sexual dysfunction in males)
H1 (histamine) antagonism
Sedation, drowsiness, weight gain, potentiation of central depressant drugs
Blurred vision, attack/exacerbation of narrow-angle glaucoma, dry mouth, sinus tachycardia, constipation, urinary retention, memory impairment
5-HT2A (serotonin) antagonism
Decreased risk of EPS
Clinical Studies With Combination Regimens.
Aripiprazole + lithium or valproic acid/valproate (VPA)/divalproex
Lamotrigine + lithium or VPA
Lamotrigine + VPA or lithium
Lamotrigine added to VPA, lithium, atypical antipsychotic (ie, clozapine, olanzapine, quetiapine, risperidone), SSRI (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline)
Changes in psychiatric rating scales
Lithium + VPA
6-month, double-blind, parallel-group maintenance trial; patients enrolled in an acute stabilization phase were eligible (N=31)
Multinational open-label study with a follow-up of up to 24 months (N=330)
Addition of VPA to lithium did not provide greater prophylactic benefit vs lithium alone67
A combination of lithium and VPA and lithium monotherapy could prevent relapse; the study could not reliably confirm nor refute a benefit of combination therapy compared with lithium monotherapy, but both lithium and lithium-VPA cotreatment were superior to VPA monotherapy66
Olanzapine + lithium, VPA, or carbamazepine
Maintenance treatment for treatment-resistant disease
Olanzapine + other antipsychotics, anticonvulsants, and/or lithium
Quetiapine + lithium or VPA
Naturalistic study followed bipolar patients for4 years (N=232)
A double-blind, placebo-controlled 12-week study; evaluated effiicacy of quetiapine as adjunct therapy with lithium or VPA in reducing alcohol consumption in bipolar I patients with coexisting alcohol dependence (N=363)
Combination of quetiapine pluslithium or VPA was more effective than lithium or VPA monotherapy in maintaining euthymia; efficacy of quetiapine monotherapy, lithium monotherapy, and combination of lithium or VPA was similar in preventing the recurrence of major depressive episodes64
Adding quetiapine to lithium or VPA did not improve measures of alcohol use and dependence compared with placebo63
Risperidone + lithium or VPA
Risperidone or haloperidol + lithium or VPA
3-week, randomized, double-blind, placebo-controlled study involving patients with bipolar disorder and a current manic or mixed episode (N=156)
Ziprasidone + lithium or VPA
SSRI=selective serotonin reuptake inhibitor.
Metabolic Pathways, Drug-Drug Interactions, and Importance of Dose Adjustment
Understanding the metabolic pathways involved in a given disease state is critical for rational treatment selection. A thorough assessment of hepatic or renal health informs dosage adjustments and the need for concomitant medications. Table 6 summarizes metabolic pathways and clinically important drug-drug interactions for medications used in BD. 7,10-12,14-16,21,74-89
Metabolic Profiles of Bipolar Medications and Potential Drug Interactions.
Potential drug-drug interactions of clinical relevance
Oxidation, hydroxylation, conjugation
Potent inducer of CYP3A4 , CYP 1A2, 2B6, 2C8, 2C9, 2C19, 3A4 enzymes.7,86 It may ↓ plasma concentrations of medications primarily metabolized through CYP3A4 (eg, acetaminophen, bupropion, olanzapine, oral contraceptives, valproate); CYP3A4 inhibitors ↑ carbamazepine levels7
β-oxidation, CYP450 system, glucurodination
Inhibits lamotrigine metabolism, increasing lamotrigine concentrations, which may result in serious toxic reactions84; coadministration with warfarin or aspirin can interfere with blood clotting83,84
Glucurodination, CYP450 system
Clearance ↑ with carbamazepine, phenytoin, phenobarbital, and primidone but ↓ with valproic acid82; plasma levels ↓ by oral contraceptives79-82
95% renal excretion
Diuretic-induced sodium loss may ↓ renal clearance of lithium, increasing levels and leading to lithium toxicity10,11; in addition, lithium toxicity can result from interactions with NSAIDs, indomethacin, piroxicam, metronidazole, angiotensin-converting enzyme inhibitors, and calcium channel blockers; acetazolamide, urea, xanthine preparations, and alkalinizing agents may lower lithium concentrations10,11
CYP1A2, CYP2D6, CYP3A4, CYP2C1987,88
Coadministration may ↑ phenytoin concentrations; concomitant administration with propranolol results in ↑ concentrations of drugs; thiazide diuretics may potentiate phenothiazine-related hypotension12
CYP2D6 > CYP3A489
Need to ↓ dose when a CYP2D6 inhibitor is given (eg, fluoxetine or paroxetine) Need to ↑ dose when a CYP3A4 inducer (eg, carbamazepine) is given and ↓ dose when a CYP3A4 inhibitor is given or a CYP3A4 inducer is discontinued78
Primarily glucurodination (UGT1A4), secondarily CYP1A214
Coadministration with fluvoxamine ↑ fluvoxamine concentrations; may enhance effects of certain antihypertensive agents14
Fluoxetine (used in combination with olanzapine)
Coadministration with other drugs that are tightly bound to protein may cause displacement of fluoxetine; coadministration with other drugs metabolized by CYP2D6 (eg, alprazolam, haloperidol, clozapine) may ↑ concentrations of these drugs; may ↑ concentrations of carbamazepine and phenytoin; coadministration with lithium may ↑ or ↓ lithium levels; potential pharmacodynamic interactions when coadministered with other centrally acting drugs or serotonergic drugs; should not be used along with an MAOI or for less than14 days after discontinuing an MAOI due to risk of serious interaction; concomitant administration with pimozide or thioridazine contraindicated due to QTc prolongation74
Coadministration with carbamazepine ↓ olanzapine levels85; and fluvoxamine ↑ olanzapine levels77,84; pharmacodynamic interactions should be considered when coadministered with other centrally acting drugs or alcohol; may potentiate effects of certain antihypertensive agents84; smoking decreases blood levels15
CYP3A4, sulfoxidation, and oxidation
CYP3A4 inhibitors (eg, fluvoxamine, clozapine) may ↑ quetiapine levels76; CYP3A4 inducers (eg, carbamazepine) may ↓ quetiapine levels; quetiapine can ↑ levels of the main active metabolite of carbamazepine; although study results conflict, valproic acid may ↑ quetiapine levels75,76
Hydroxylation, CYP2D6, CYP3A4
Potent CYP2D6 inhibitors (eg, fluvoxamine, fluoxetine, paroxetine) can ↑ risperidone plasma levels in poor and extensive metabolizers77; coadministration with carbamazepine ↓ risperidone and active moiety levels and ↑ carbamazepine levels84
Aldehyde oxidase > CYP3A4
Carbamazepine coadministration may ↓ ziprasidone levels21; potent CYP3A4 inhibitors (eg, ketoconazole) may ↑ ziprasidone levels21; should not be used with other drugs that cause QT prolongation; may enhance effects of certain antihypertensive agents21
CYP = cytochrome P450; MAOI = monoamine oxidase inhibitor; NSAIDs = nonsteroidal anti-inflammatory drugs; QTc = corrected QT.
Lithium is removed from the body by the kidney and eliminated unchanged in the urine.90 Thus, an individual with renal dysfunction is not an ideal candidate for lithium treatment; however, lithium does not undergo hepatic metabolism and may be suitable for patients with compromised hepatic function. Carbamazepine is infrequently used for the management of BD primarily because it induces cytochrome P450 (CYP) enzymes and is therefore associated with drug-drug interactions.6,7 Carbamazepine reduces its own levels and is also a heteroinducer, influencing other medications that patients with BD may be receiving.7,91 Further, carbamazepine has several Black Box warnings (eg, hematologic abnormalities and dermatologic reactions) that limit its use.6,7 Lamotrigine is approved for the maintenance phase of BD and appears most beneficial in preventing depressive episode recurrence.9,92 It is frequently used in combination with other mood stabilizers or antipsychotic agents for the management of BD. Exceptionally careful upward titration is key to lamotrigine use due to the risk of occasionally fatal Stevens-Johnson syndrome that is dose- and titration-rate–dependent. The Black Box warning came about in part from adverse events related to coadministration of lamotrigine with valproic acid, which elevates lamotrigine levels by as much as 100%, especially at higher than recommended starting doses.92
When a patient is using a hepatic CYP enzyme inducer like carbamazepine, the dose of aripiprazole—as with all hepatically metabolized antipsychotics—should be appropriately increased.13 Conversely, if an individual is taking a CYP3A4 inhibitor such as ketoconazole, or a CYP2D6 inhibitor such as fluoxetine or paroxetine, the aripiprazole dose should be appropriately reduced.13 Asenapine is unique because it is a substrate for UDP glycosyltransferase 1 family, polypeptide A4 (UGT-1A4), and CYP1A2 and is, therefore, likely to be influenced by CYP1A2 inhibitor antidepressants such as fluvoxamine.14 Further, because cigarette smoking induces CYP1A2, smokers on average may require a higher dose of olanzapine and clozapine than nonsmokers to compensate for the lower medication levels.93 Asenapine levels are not influenced by smoking.14
For individuals on multiple medications that are metabolized by CYP3A4, drug-drug interactions with quetiapine may pose a problem. Interactions between risperidone and agents that inhibit CYP2D6 (eg, fluoxetine, paroxetine) are clinically important since higher levels of risperidone may produce extrapyramidal side effects.94 Drug-drug interactions are generally less likely with ziprasidone, given its alternative metabolic pathway involving aldehyde oxidase.90 Selecting from among the atypical antipsychotics will depend to some extent on idiosyncratic metabolic factors and concomitant medications that increase the risk of drug-drug interactions (Table 6).
Available Formulations of Medications for Bipolar Disorder
Understanding available formulations (Table 7)6-8,10-18,20,21,92,95-97 and dosages (Table 8)84 can help guide the selection of medications. The controlled-release (CR) form of lithium will prove useful in patients who will benefit from up to a 4-hour delay in maximum concentration (Cmax).98 Lithium syrup with 1 hour to Cmax is also available.99 The CR dosage is recommended for patients who cannot tolerate the gastrointestinal side effects of lithium. With valproic acid, the extended-release (ER) formulation has a delayed time to peak and a lower bioavailability versus the delayed-release (DR) formulation, and the ER formulation can be given once daily.100 Finally, the 10% to 20% reduction in bioavailability with the ER formulation will require patients switching from DR to have a dosage increase.101
In addition to their unique drug-drug interaction profiles, antipsychotics vary by available formulations as well. Short-acting injectable formulations are available for chlorpromazine, haloperidol, aripiprazole, olanzapine, and ziprasidone, and are appropriate for patients with acute mania. While injectable haloperidol and ziprasidone are not indicated for BD, they may be used with or without lorazepam for the management of acute mania. For individuals who require a long-acting injectable agent due to preference or adherence issues, the only Food and Drug Administration (FDA)-approved agent is long-acting risperidone.20 Other nonapproved long-acting injectable formulations are available and may be used in the clinical setting. These include haloperidol decanoate, fluphenazine decanoate, paliperidone long-acting injection, and olanzapine pamoate. The extent to which these nonap-proved agents are beneficial is currently unclear, as at present there are few data on efficacy from clinical studies.
Recommendations for switching from an oral antipsychotic regimen to a long-acting antipsychotic differ. With haloperidol or fluphenazine, a loading dose of depot medication is usually given and the amount of overlap with oral administration should be minimal.102,103 However, when using the long-acting dosage form of risperidone, oral administration and injection should overlap for at least the first 3 weeks.20 In clinical practice, a 4- to 6-week overlap with oral administration may be needed for individuals to derive maximum benefit and to avoid the risk of relapse. With long-acting risperi-done, only 1% of drug is released during the first 3 weeks of treatment. Additional drug is then released slowly until a peak is reached during the next week and a half. Risperidone concentrations peak about 4.5 weeks after the initial injection.20
In contrast, the long-acting dosage forms of paliperidone and olanzapine do not require overlap and provide an option that achieves therapeutic drug levels quickly without a need for oral administration.97,104 However, with the long-acting injectable paliperidone, a second injection at Week 1 is required once to achieve therapeutic blood levels.104 It is important to remember that these two agents are not approved for BD, but rather for schizophrenia.
Available Formulations of Agents Approved for Bipolar Disorder.
Tablet, chewable tablet, ER or XR capsule, ER or XR tablet, suspension
Divalproex/ valproic acid8,96
Capsule, DR capsule, sprinkle capsule, DR and ER tablet, oral solution, syrup, short-acting injectable
Tablet, chewable dispersible tablet, orally disintegrating tablet, ER tablet
Tablet, CR tablet, capsule, syrup
Tablet, short-acting injectable
Tablet, orally disintegrating tablet, solution, short-acting injectable
Tablet, orally disintegrating tablet, short-acting injectable, long-acting injectable
Tablet, XR tablet
Tablet, orally disintegrating tablet, solution, long-acting injectable
Capsule, short-acting injectable
CR = controlled release; DR = delayed release; ER = extended release.
a Only Equetro® ER capsules approved for BD.
b Only Depakote® DR capsule, DR and ER tablets approved for manic episodes associated with BD.
c Not currently approved for BD.
d Approved for acute agitation associated with BD.
Equetro is a registered trademark of Validus Pharmaceuticals.
Depakote is a registered trademark of Abbott Laboratories.
Dosing and Therapeutic Drug Monitoring for Drug Use in Bipolar Disorder.84
Daily dose range (mg/d)
Therapeutic plasma level range
Additional notes on therapeutic drug monitoring
Serum levels of carbamazepine should be measured 12 hours after a dose but do not correlate with clinical response
CSF levels of the 10-, 11-epoxide metabolite are associated with clinical response
Obtaining serum levels may provide guidance related to adherence or to whether an individual may be a poor or rapid metabolizer
Initial levels may decrease with time, as autoinduction of its own metabolism develops across time
Serum concentrations are best obtained at trough, 12 hours after valproic acid 2x/d
ER formulation serum concentrations are some 25% greater than DR formulation equivalents per unit time
ER serum levels of 100 μg/mL, translate to 75 μg/mL with the DR formulation
When using the ER formulation, check serum level at 18–20 hours. Loading with 20–30 mg/kg is possible
Maintenance dose usually at 20 mg/kg
BMI = body mass index; CSF = cerebrospinal fluid; DR = delayed release; ECG = electrocardiogram; ER = extended release; HgbA1c = glycosylated hemoglobin.
Patient-Specific Factors Influencing Therapeutic Selection Strategies
In addition to drug-specific factors, patient-specific factors must be considered when selecting treatment. For example, lithium should be used with caution in patients with a history of cardiovascular disease or patients who are dehydrated due to an effect on the atrioventricular node and the adverse impact on lithium concentration in the dehydrated state.11,105 In addition, lithium may influence thyroid function, potentially leading to hypothyroidism, so longitudinal monitoring of thyroid function and levels of concomitant thyroid medications is necessary.11 Because carbamazepine and valproic acid are sedating agents, concomitant use with other drugs that have sedative properties increases the risk of additive or synergistic effects and should therefore be managed with caution.6-8 Valproic acid has been associated with hepatic failure and pancreatitis; as such, lithium may be a preferable substitute for patients with hepatic impairment.8 Olanzapine, quetiapine, and chlorpromazine are all relatively sedating compounds. Other antipsychotics, such as aripiprazole, risperi-done, and ziprasidone are less sedating and should be considered when sedation is an issue.106,107
Teratogenicity has been associated with the anticonvulsants and lithium, despite the relatively minimal risk of lithium. The labeling for valproic acid contains a Black Box warning related to neural tube defects in the offspring of pregnant women who received this agent.8 This warning may prompt selection of alternative therapies, such as antipsychotic agents, for the management of BD in young female populations of childbearing age and those who are pregnant or desire to become pregnant, although the safety of antipsychotics during pregnancy has not been conclusively established. A recent report indicates that prenatal exposure to valproic acid may affect the long-term developmental outcome of children. In this study, the mean full-scale IQ (FSIQ) of children who were exposed to valproic acid in utero was 83.9 (95% confidence interval [CI], 64.2-103.6), compared with 102 (95% CI, 90-116) in the control group.108
Concluding Remarks and Future Directions
Our understanding of the mechanisms by which mood stabilizers and antipsychotics achieve their effects in patients with BD has expanded,
which may help identify novel therapeutic targets. Despite such advances, treatment remains inadequate for many patients with BD. Most patients require a combination of medications. Therefore, considering drug-drug interactions and metabolic effects of individual agents is critical when selecting therapy. To improve prognosis and outcomes and to minimize the burden of disease symptomatology, a focus on early and long-term treatment is needed.
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