Psychopharmacotherapy during the childbearing and perinatal periods
Psychopharmacotherapy in children and adolescents
The embryo, fetus, and neonate:
Spontaneous abortion or premature labor
Toxicity or withdrawal symptoms
Morphological teratogenicity
Breastfeeding from a mother on a psychotropic
Future behavioral teratogenicity, because psychotropics target the brain and the effects on fetal brain morphogenesis may not be apparent for several years
The mother:
Premenstrual dysphoric disorder (PMDD)
Polycystic ovarian syndrome (PCOS)
Decreased or increased likelihood of conception
Emotional stress associated with pregnancy (1)
Both:
Alterations in stress-related systems (e.g., neuroendocrine, immune/inflammatory, cardiovascular) perhaps mediated by placental corticotropin-releasing hormone (CRH) (2)
The consequences of an untreated or inadequately managed mental disorder
Postpartum episodes (e.g., depression, psychosis)
Clustering of mood and anxiety disorders during the childbearing years
High prevalence of mood, behavioral, and cognitive symptoms during pregnancy, although depression prevalence during pregnancy is comparable to that of the nongravid state (7)
Bipolar disorder (BPD), which may destabilize during pregnancy
become pregnant or produce adverse effects in both mother and child during and after pregnancy.
TABLE 14-1 FOOD AND DRUG ADMINISTRATION RISK CATEGORIES | ||||||||||||||||||||||
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Avoid low-potency phenothiazine antipsychotics, if possible, during the period of highest risk for teratogenicity (i.e., 4 to 10 weeks after conception) and near term because of possible maternal hypotension and possible neonatal adverse effects
Taper antipsychotics, if possible, 2 weeks before the estimated date of confinement to minimize withdrawal effects in the neonate
Resume the antipsychotic immediately postpartum in chronically psychotic women to minimize the possibility of a postpartum episode
Use higher potency agents (e.g., haloperidol) to minimize sedation, orthostasis, gastrointestinal slowing, tachycardia, and morphological teratogenicity (17)
Avoid clozapine, if possible
Immediately discontinue the antipsychotic and use bromocriptine to manage a neuroleptic malignant syndrome, if it develops
During breastfeeding, SGAs such as risperidone and quetiapine are preferable while clozapine and olanzapine should be avoided (18,19)
Avoid routine prophylaxis with antiparkinsonian agents, including benztropine, diphenhydramine, and amantadine, all of which are associated with congenital anomalies. Calcium supplementation may be a useful alternative, and propranolol or atenolol may be used for akathisia if cardiovascular status is stable (12,20).
(e.g., diabetes) versus those with a low-risk pregnancy (21,22 and 23). Women on antidepressants who stop when they become pregnant may be at substantially greater risk of relapse than those who remain on their medication (24). Further, a recent national survey found a significantly higher prevalence of major depression in postpartum versus nonpregnant women (25). In this regard, it is important to remember that depression itself may also have a deleterious impact on later development.
Nondrug approaches (e.g., cognitive-behavioral therapy (CBT), interpersonal psychotherapy, bright light therapy) are always preferable (28,29 and 30)
If necessary, agents that have been better studied and have fewer adverse effects are preferred (e.g., fluoxetine, citalopram, escitalopram) (31,32 and 33)
If possible, paroxetine should be avoided due to a greater risk for congenital cardiac malformations with first trimester exposure (34,35). If exposed to this agent during early pregnancy, fetal echocardiography should be considered.
Nortriptyline and desipramine may be the TCAs of choice, given their extensive assessment during pregnancy and well-known therapeutic concentrations, which should be monitored (36)
Dose increase may be necessary due to increased turnover in the second half of pregnancy (37)
If an antidepressant is stopped during pregnancy, it should be gradually tapered to avoid maternal or fetal withdrawal syndromes
If clinically possible, drug tapering or dose reduction should begin 3 weeks before the estimated date of conception (EDC) (12,38)
Electroconvulsive therapy (ECT) modified for pregnancy may be a reasonable choice for acutely suicidal or psychotically depressed patients (39) (see Chapter 8)
Those with a prior history may be more susceptible to postpartum depression; psychotherapy alone or combined with maintenance antidepressant therapy may benefit such patients and should be done with a team approach (e.g., psychiatrist, obstetrician, pediatrician) to obtain the optimal outcome (40,41,42,43 and 44)
There should be frank discussion about family planning
The risk-to-benefit ratio must be carefully weighed when contemplating whether to initiate, continue, or withdraw drug therapy (49)
Lithium, VPA, and CBZ (pregnancy category D) should be avoided, especially during the first trimester, if clinically feasible
Consider alternative therapies, such as lamotrigine (pregnancy category C), SGAs, or ECT modified for pregnancy
If lithium is necessary during the first trimester, sonography can clarify the presence and severity of anomalies such as Ebstein’s tricuspid valve defect
Lithium should be given in smaller, divided doses to avoid higher peak plasma levels
If the patient is exposed to VPA or CBZ, the presence of neural tube defects should be evaluated (e.g., serum alpha protein, amniocentesis, ultrasound), especially if they are used together
If anticonvulsants are used, daily folate (up to 4 mg/day) may decrease the risk of neural tube defects, and vitamin K (20 mg/day) may prevent drug-induced bleeding
With BPD, the increased risk of a postpartum episode warrants the resumption of medication compatible with lactation soon after delivery (50).
Alternative, nondrug management of anxiety whenever possible (e.g., behavioral therapies, interpersonal psychotherapy, relaxation techniques, cessation of stimulants such as caffeine)
Consider an SSRI (except paroxetine) during the first and second trimesters
Avoid BZDs in first trimester, if possible
If a BZD is necessary, consideration of lorazepam because of its possible lower accumulation in fetal tissue; but avoid the use of BZDs until after the 10th week of gestation (particularly diazepam) to preclude oral defects
Gradual tapering of a BZD before delivery to minimize any neonatal withdrawal phenomena
Avoidance of diphenhydramine because of both fetal teratogenic and withdrawal complications (52)
Reversal of fetal or neonatal toxicity with flumazenil (53)
Risks associated with continued breastfeeding
Risks associated with stopping medication
Polypharmacy, which should be avoided and the lowest effective dose used
Weaning if the neonate experiences adverse effects and/or sustained drug plasma levels (typically a <10% neonate-calculated dose exposure is considered safe)
often requiring the use of various psychotropics. Unlike the much milder and more prevalent premenstrual syndrome (PMS), PMDD is characterized by
Persistent irritability or anger
Tension, marked anxiety
Dysphoria, hopelessness, self-deprecation
Mood lability, fatigue, decreased energy
Dyssomnia
Appetite fluctuations
Feelings of being out of control
Other physical symptoms
Lithium
Alprazolam
Various antidepressants
Reproductive dysfunction:
Ovulatory dysfunction
Menstrual disorders
Infertility
Miscarriage
Metabolic derangements:
Insulin resistance, hyperinsulinemia
Impaired glucose tolerance
Dyslipidemia
Noninsulin-dependent diabetes
Emotional sequelae due to factors such as
Hirsutism
Female pattern, androgenic alopecia
Acne
Long-term health effects, such as
Cardiovascular disease
Endometrial hyperplasia or malignancy
Obstructive sleep apnea
Obesity
Hereditary disorder of insulin action (72)
Hypothalamic-pituitary axis dysfunction
Ovarian defects
Epilepsy
Antiepileptic drugs (e.g., VPA, others)
Diet and exercise to reduce weight
Supportive or group psychotherapy to manage the psychological impact
Agents such as oral contraceptives to reverse hyperandrogenism
Agents such as clomiphene to increase fertility
Insulin-lowering medications (e.g., metformin) to regulate glucose levels
If clinically feasible, consideration of agents other than VPA to manage epilepsy or BPD (see Chapter 10)
psychopharmacology than ever before. The full impact of this increased activity, however, will take several years to realize due to the lag time between initiating and completing such trials. As data from these pediatric clinical trials are published, they are subjected to more scrutiny, leading to augmented scientific rigor (83,84 and 85). Some of the minimum standards include providing a consort chart (83), details of randomization methods (84), explanations of varying methodology in calculating effect sizes (85), and improved methods of eliciting adverse events that are central to patient safety (84). Several newly completed and published studies are summarized in this chapter.
Do the needs and desires of the child or adolescent and the parent conflict or are they in synchrony?
What is the patient’s social and family situation and how will it influence treatment outcome?
Will the parent or guardian be able to assist with the administration and monitoring of the medication?
What other forms of treatment may be needed (e.g., education about the condition and about better behavioral management techniques, family therapy, or individual psychotherapy)?
What does the patient think about his or her condition, the need for treatment, and the specific treatment being recommended?
How will the treatment affect the patient’s selfconcept and relations with others?
How is the patient doing in school? (e.g., if there are significant changes in level of functioning, the time course and magnitude of the changes should be carefully assessed).
Does the child or adolescent have a condition of sufficient severity to warrant medication?
Have all the options been reasonably discussed and their relative merits and liabilities weighed?
What outcome parameters will be used to document the potential beneficial and adverse effects of the medication?
Is the addition of a second or third medication necessary (e.g., if the first treatment fails, should it be discontinued rather than resorting to polypharmacy)?
TABLE 14-2 DEVELOPMENTAL PATTERNS FOR SPECIFIC DRUG-METABOLIZING ENZYMES | ||||||||||||||||||||||||
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what might be optimal for a child or adolescent patient. This is because younger patients are either more or less sensitive to the beneficial or adverse effects of the drug (and thus might need a higher or lower concentration than adults to achieve an optimal response). Nevertheless, TDM serves as a reasonable reference point in the absence of more definitive efficacy and safety data in children and adolescents. Using TDM in this manner, the prescriber then carefully adjusts the dose based on clinical assessment of safety and efficacy. It is also prudent to divide the daily dose more frequently than in adults to avoid excessively high peak plasma drug concentrations that may be associated with increased tolerability and safety problems.
TABLE 14-3 IMPORTANT FEATURES OF COMMON STIMULANTS USED TO TREAT ATTENTIONDEFICIT DISORDER IN CHILDREN AND ADOLESCENTS | |||||||||||||||||||||||||||||||||||||
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with a major depression (41%), BPD (24%), or, less frequently, schizophrenia (14%). The presence of formal thought disorder (e.g., loose associations) in the absence of a developmental disorder, particularly in children older than 7 years, may indicate a schizophrenic spectrum illness (96). In this context, a retrospective study of adult schizophrenia (95) and two prospective studies of younger subjects (ages 16 to 30 years and 12 to 45 years) suggested that the presence of brief psychotic episodes, perceptual disturbances, thought disorganization, unusual thoughts, poor functioning, and blunted or inappropriate affect combined with a family history of psychosis increased the risk for schizophrenia and related psychotic disorders (102,103). An important caveat is that patients with mood disorders may present with schizophrenic-like thought disruption (91,92,99,100), making appropriate diagnosis and treatment more challenging. Evidence indicates that childhood-onset schizophrenia demonstrates distinct cortical gray matter loss during adolescence, which appears to be an exaggeration of the normal cortical gray matter developmental pattern and eventually mimics the pattern seen in adult-onset cases as the children become young adults (104). These cortical gray matter changes in childhood-onset schizophrenia may be diagnostically specific, unrelated to the effects of medications, and also are shared by healthy full siblings. This suggests a genetic influence on the abnormal brain development.
Early antipsychotic medication intervention may be associated with a better long-term outcome (105,106,107,108 and 109)
The use of SGAs with their lower rate of particular adverse effects makes early intervention more acceptable
The deficit process (or negative symptoms) is usually present at the first psychotic episode (110). This may mean that the symptoms begin prior to the onset of illness as currently defined. In this context, accurate early identification and aggressive intervention may arrest the transition into a full disorder
Early presentation of psychosis often causes severe distress on the family system, which also requires early treatment interventions
Brief intermittent psychosis. One or more positive symptoms such as hallucinations, suspiciousness, or unusual thought content (scores of >3 to 4 on these Brief Psychiatric Rating Scale [BPRS] items) in the last 3 months, for at least several minutes a day, at least once a month.
Attenuated positive symptoms. At least one symptom of schizotypal disorder and one symptom of psychosis such as hallucinations, suspiciousness, or unusual thought content in subdued form (lower scores of 1 to 2 on these BPRS items) in the past year and present at least once per week in the last month.
Genetic risk and recent deterioration. Having a first-degree relative with a history of any psychotic or schizotypal personality disorder and a drop of >30 points on Global Assessment o f Functioning (GAF) for at least 1 month.
excluded affective psychosis. The term “ultra-highrisk” subjects is favored over prodrome by McGorry (103), as it does not imply inevitable progress to a full disorder, whereas the term “prodrome” is typically used by McGlashan (102). In addition, neither of these studies included measures to identify affective symptoms despite compelling evidence that psychosis is common in pediatric BPD (98,112,113,114,115 and 116).
Gastrointestinal side effects (nausea, constipation, stomatitis)
Cognitive disturbances (in particular the low-potency antipsychotics)
Blood dyscrasias (e.g., agranulocytosis, thrombocytopenia)
Hepatic abnormalities (e.g., increase in the liver transaminases, cholestatic jaundice)
Dermatological problems (e.g., atopy, photosensitivity)
Eye complications (e.g., chlorpromazine and thioridazine at high doses may induce lenticular and retinal pigmentation and retinitis pigmentosa)
Dyslipidemia
Neuroleptic malignant syndrome (NMS)
and molindone more neuromotor-related complications.
and/or who pose a suicidal or homicidal threat should be offered indefinite maintenance therapy (120,122,123).
movements before starting an antipsychotic is important because dyskinesias or other movement disorders may exist before treatment, indicating an increased propensity to develop EPS and/or TD (120,121 and 122). Before prescribing an SGA, baseline and subsequent neurological exams are conducted to rule out dyskinesia. In addition, we recommend a baseline CBC plus differential, fasting glucose level, liver function tests, lipid profile, ECG, and ascertainment of body mass index. For clozapine, we suggest a baseline EEG and ECG with routine monitoring (e.g., every 6 months). Since the SGAs are metabolized by CYP 450 isoenzymes, it is important to monitor potentially relevant pharmacological interactions with other medications metabolized by this system.
Irritable mood can be present instead of depressed mood
Failure to gain expected weight equals weight loss criteria
Dysthymic disorder (DD) can be 1-year in duration in children as opposed to 2 years in adults
Since a mixed presentation of depressive plus manic symptoms is common in pediatric BPD, clinicians can misinterpret it as MDD (152). Thus, it is particularly important to inquire about manic or hypomanic symptoms that would dictate treatment with a mood stabilizer as opposed to an antidepressant.
of Montgomery-Asberg Depression Rating Scale (MADRS) responders (i.e., at least 50% reduction from baseline) on paroxetine and placebo were similar and not statistically different at end point (p < 0.70). A similar result was obtained for change from baseline score on the Kiddie-Schedule for Affective Disorders and Schizophrenia for SchoolAge Children (K-SADS-L) depression subscale. In general, results differed by age, with patients older than 16 years demonstrating a greater response to active treatment. This age group also reported more adverse experiences relative to placebo than younger adolescents. Emslie et al. (162) also studied youths (7 to 17 years) with MDD who were randomized to receive paroxetine (10 to 50 mg/day) or placebo for 8 weeks. The primary efficacy measure was change from baseline in the Children’s Depression Rating Scale-Revised (CDRS-R) total score. Adjusted mean change scores from baseline for patients receiving paroxetine and placebo were —22.58 and —23.38 points, respectively (p < 0.684). Increased cough (5.9% vs. 2.9%), dyspepsia (5.9% vs. 2.9%), vomiting (5.9% vs. 2.0%), and dizziness (5.0% vs. 1.0%) occurred in ≥5% of the paroxetine group and at least twice that of the placebo group. In this trial, paroxetine was no more efficacious than placebo for treating pediatric MDD.
(i.e., 7.1% vs. 3.2%). The discontinuation rate due to adverse events was 2.6% with escitalopram and 0.6% with placebo. Serious adverse events were reported in 2.6% and 1.3% of escitalopram and placebo patients, respectively. The incidence of suicidality was similar for both groups.
Patients should be observed carefully for any emerging suicidal ideation, especially in the first few weeks of treatment.
No baseline laboratory work is currently indicated (140).
Except for lower initial doses, the administration of SSRIs in children and adolescents is similar to adults.
Start at lowest possible dose, increasing weekly by 1 mg/kg/day for fluoxetine and citalopram and 3 mg/kg/day for sertraline and fluvoxamine, or less based on tolerability. Negative results with paroxetine suggest that this drug should not be used.
Optimal time period for desired response is at least 6 weeks.
TABLE 14-4 IMPORTANT ISSUES WITH COMMONLY USED ANTIDEPRESSANTS IN CHILDREN AND ADOLESCENTS | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
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A different SSRI
A different SSRI plus CBT
Venlafaxine (150 to 225 mg)
Venlafaxine plus CBT
stabilizers (see Chapter 10). Further, it is critical to adjust the dose of oral contraceptives when combined with agents such as CBZ and lamotrigine to avoid an inadvertent pregnancy.
concentration, and impulsivity (189). Recent data also indicate that preschool offspring of parents with BPD have an elevated risk of ADHD and greater levels of subthreshold mania and depressive symptoms (190).
observed with divalproex XR based on change in mean YMRS baseline score (i.e., divalproex ER, -8.8 [n = 74]; placebo, -7.9 [n = 70]). Divalproex was also similar to placebo based on the incidence of adverse events. In the long-term study, YMRS scores decreased modestly (2.2 points from baseline) in 66 participants. The most common adverse events were headache and vomiting. These results do not provide support for the use of divalproex XR in the treatment of youths with bipolar I disorder, mixed or manic state.
a Clinical Global Impressions-Bipolar Disorder [CGI-BP] severity score of 3). However, 69% of the adolescents had a 7% or greater increase in body weight and 40.5% of participants had abnormally high prolactin levels. Thus, metabolic adverse effects limit the utility of olanzapine as an acute and maintenance agent for youth withBPD (225).
somnolence, EPS, fatigue, nausea, akathisia, blurred vision, salivary hypersecretion, and dizziness. Rates of somnolence (aripiprazole, 22.9%; placebo, 3.1%; NNH = 5.1); extrapyramidal disorder (aripiprazole, 19.8%; placebo, 3.1%; NNH = 6.0); akathisia (aripiprazole, 9.7%; placebo, 2.1%; NNH = 13.2); salivary hypersecretion (aripiprazole, 5.6%; placebo, 0%; NNH = 17.9); and clinically significant (≥7%) weight gain appeared to increase with the aripiprazole dose (i.e., 10 mg, 4.0%; 30 mg, 12.3%; placebo, 4.6%; NNH = 28). Mean weight gain was modest and statistically similar across groups (10 mg, —0.55 kg; 30 mg, —0.90 kg; placebo, —0.54 kg). Discontinuation rates due to adverse effects were 7% with aripiprazole and 2% with placebo.
80% with divalproex sodium plus risperidone. Defining remission as ≥50% YMRS change score from baseline; an end point CGI-I of ≤2; and an end point C-GAS of ≥51; 45% and 60% remitted, respectively. Weight gain, nausea, sedation, and gastrointestinal upset were the most frequent adverse effects, with no significant group differences.
comparing lithium to divalproex sodium over 18 months in 60 bipolar I and II, stable, euthymic subjects. Thirty children and adolescents (5 to 17 years) were enrolled, in each arm. Stimulants were used in 58.3%. At the end of 18 months, only three subjects remained in each arm. Time to relapse and premature discontinuation for any reason did not differ between the lithium or divalproex sodium groups. Median survival in the study was 114 days on lithium and 112 days on divalproex sodium. Subjects with higher baseline YMRS scores discontinued earlier. Adverse effects with lithium included emesis and enuresis (30% each). Stomach pain and headache (23.3% each) were the most common adverse effects in the divalproex sodium group.
Separation anxiety disorder
Generalized anxiety disorder (GAD)
Social phobia (i.e., social anxiety disorder)
Specific phobia
Panic disorder (with and without agoraphobia)
Agoraphobia without panic disorder
Posttraumatic stress disorder (PTSD)
Obsessive-compulsive disorder
manifests in children and adolescents. For example, anxious symptoms may present as crying, tantrums, irritability, oppositionality, argumentativeness, and other behavioral problems in addition to the core features of fear, worry, and avoidance. The DSM-IV-TR adjusts to account for these differences between child and adult manifestations of anxiety disorders. For example, children can be diagnosed with specific phobia if anxious symptoms include crying and tantrums. Also, it is not necessary for children to recognize that their fear is excessive or unreasonable to meet criteria for social phobia or specific phobia. Furthermore, the criteria for GAD require three associated symptoms for adults but only one for children. School-aged children and adolescents display the discrete subtypes of anxiety disorders proposed in the DSM-IV-TR, but anxiety symptoms in preschoolers may be more diffuse and less distinct from one another (239).
SAD often presents at ages 6 to 9 years
GAD presents at any age, but most often at ages 10 to 12 years
Social phobia presents at age 12 years and older
versus placebo (29%) group (p < 0.05) (245). Fluvoxamine was dosed to a maximum of 250 mg/day in children younger than 12 years and 300 mg/day in adolescents. Social phobia and severity of illness predicted a less favorable outcome (258). In a subsequent controlled trial, youth with GAD, SAD, and/or social phobia and significant functional impairment were randomized to fluoxetine (20 mg/day) or placebo (242). Youths (n = 74) with social phobia and GAD responded significantly better to fluoxetine than placebo (p < 0.05). Youths with severe SAD, however, showed only a trend toward improvement on fluoxetine. Overall, there was only partial resolution of symptoms in about half of the treatment group in this fixed dose study. Fluoxetine was well tolerated.
α-Agonists. In clinical practice, guanfacine (1 mg up to three times a day) or clonidine (0.1 mg up to three times a day) is combined with an SSRI when there is significant associated autonomic arousal and/or restlessness, though no controlled studies exist. An ECG and careful monitoring of pulse and blood pressure are recommended with these medications. It is important to discuss the possibility of rebound hypertension on their discontinuation with patients and families, so that medication is not stopped abruptly. Youth with comorbid Tourette disorder, trichotillomania, other impulse control disorders, ADHD, BPD, or PTSD may benefit from these medications as well.
Regardless of presenting problems, screen routinely for anxiety disorders
Anxiety disorders in children and adolescents have frequent comorbidities that must also be addressed
Major risk factors (e.g., parental anxiety, temperament, parenting styles, attachment, negative life events, and stressors) and protective factors (e.g., coping style) are identified for childhood anxiety disorders
Treatment should incorporate empirically supported interventions such as CBT and SSRIs as detailed earlier
No specific SSRI is recommended, and there is no apparent difference in efficacy for anxiety disorders among the SSRIs
SNRIs may be an alternative approach.
Fluvoxamine (270)
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