A comprehensive review introduction



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Table 17: Physiologic changes to the liver in older adults

Another pharmacokinetic consideration to take into account is the distribution of drugs via protein (albumin) binding. Like renal clearance, the amount of protein in the body is governed by a number of conditions. Generally, older adults are more likely to suffer from hypoalbuminemia due to any of the two main conditions:

1) Malnutrition: lack of protein in the diet


    1. Increased excretion of albumin resulting from:

    • Renal (kidney) dysfunction

    • Liver disease such as cirrhosis or hepatitis

    • Heart disease: leads to congestive heart failure, or pericarditis

    • Gastrointestinal disorders: reduces protein absorption

    • Cancer such as sarcoma or amyloidosis 

    • Medication side effects 

    • Infections such as tuberculosis

The body can only use non-protein bound drugs. Therefore, clinicians will do well to consider the comorbidities of geriatric patients prior to prescribing psychoactive drugs.

Decreases in protein-binding results in an increase in circulating free drug fractional amounts; and, hence, its effects. An example of a highly protein bound (>90%) drug is phenytoin (Dilantin). Its use in the setting of hypoalbuminemia in an elderly patient requires dosage adjustment and cautious titration after administration of the initial dose. Usually, a total daily dose of 3 mg/kg is appropriate in this case. Due to the poor correlation of the total drug level with clinical response and risk of adverse effects, an appropriate therapeutic range may be 5–15 mcg/mL rather than the 10–20 mcg/mL recommended for young adults (119).

Also, if phenytoin (Dilantin) is administered concurrently with diazepam, the latter displaces the former from plasma proteins, resulting in an increased plasma concentration of free phenytoin and an increased likelihood of unwanted effects (119).

Other considerations to keep in mind when dealing with mentally predisposed geriatric patients are adherence to therapy, medication errors, and safety and efficacy problems. Clinicians and pharmacists need to make it easy for the patient. They need to go the extra mile with this population group using certain measures such as:


  • Ease of administration

  • Possible dose reduction

  • Avoidance or reduce medications that produce visual and motor impairment

Pregnancy

There are two types of women that fall into this population group; women who were already on psychoactive drugs when they fell pregnant and the ones who started the medication during pregnancy. A good reference is the Harvard women’s health website at http://www.womensmentalhealth.org/.

Contrary to popular belief, the hormonal changes do not naturally protect women from mental disturbances during pregnancy. Studies in the last few years have dispelled this myth and confirm that up to 20% of women suffer from stress, mood and anxiety during gestational and postpartum periods. These difficult diagnoses pose tricky challenges to the mother, baby and the clinician during the entire delicate transition. The management approach requires a balance between keeping the disorder under control and maintaining the health of the mother and the growing fetus.

For women already on psychoactive medications, there are 3 general guidelines that are usually followed:


  1. Cessation of pharmacotherapy: This is a common approach given that it minimizes fetal exposure to psychoactive drugs during its most vulnerable period of development (1st trimester). But it is not always the best approach because psychiatric instability is not a benign condition; it poses a risk to the fetus too. There have been reports of higher rates and risk of relapse in women with bipolar disorder who discontinued their mood stabilizers than those who maintained treatment (37.0%). Optimally, the clinician should present the risks and benefits of this approach to the patient so the latter can share the responsibility of making well-informed decisions regarding the treatment (120).




  1. If the risks posed by the first option outweigh the benefits, drugs that have long history of relative safe use in pregnant women should be used. The FDA Pregnancy Category Designations introduced in 1975 can be used in this instance though it is important to be aware of its limitations. For one, the category designations often lacked sufficient human data. Second, there is no clear differentiation between categories C and D (120).

A systematic review on the use of first and second generation antipsychotics during early and late pregnancy found that the latter was more likely associated with gestational metabolic complications and higher than normal birth weight of babies compared with the former. Another study reports that the drug-induced weight gain and visceral-fat accumulation of second generation antipsychotics in non-pregnant women also applies to their pregnant counterparts, exposing them to higher risks of gestational diabetes, hypertension and pre-eclampsia (122) (123).

The teratogenic risk of amisulpride, ziprasidone, and sertindole is considered unknown due to insufficient human data. Clozapine, another second generation antipsychotic, is known to cause agranulocytosis in both pregnant and non-pregnant populations. The risk of infection to the baby and mother is therefore increased, meriting careful monitoring of WBC counts for the next 6 months after initiation of therapy. In contrast, the first generation antipsychotics, haloperidol and chlorpromazine, are associated with fetal malformations (mostly limb defects) and spontaneous abortions, respectively (121).

Lithium is generally avoided in pregnancy. It is associated with high risk (13 fold) of heart malformation when used during the 1st trimester of pregnancy. When used in the 3rd trimester of pregnancy, it may cause lethargy and listlessness in babies accompanied by irregular suck and startle responses. Additionally, it may cause congenital hyperthyroidism and poor oxygenation resulting in the appearance of “blue babies”. When used in the second trimester, lithium is safe. It is contraindicated in breastfeeding women since it enters the breast milk and causes unwanted side effects on babies (124).

The guideline, Use of Psychiatric Medications During Pregnancy and Lactation, published by the American College of Obstetricians and Gynecologists (ACOG) in 2008, issues the following recommendations and conclusions based on good and consistent scientific evidence (Level A) (125):


  • Lithium exposure in pregnancy may be associated with a small increase in congenital cardiac malformations, with a risk ratio of 1.2 to 7.7.



  • Valproate exposure in pregnancy is associated with an increased risk of fetal anomalies, including neural tube defects, fetal valproate syndrome, and long term adverse neurocognitive effects. It should be avoided in pregnancy, if possible, especially during the first trimester.



  • Carbamazepine (Tegretol) exposure in pregnancy is associated with fetal carbamazepine syndrome. It should be avoided in pregnancy, if possible, especially during the first trimester.



  • Maternal benzodiazepine use shortly before delivery is associated with floppy infant syndrome.

On the other hand, there are 5-30% of women who reportedly suffer from depression at the onset and during perinatal period. Untreated depression leads to substance and alcohol abuse, and poor pregnancy outcomes such as inadequate prenatal care, low birth weight and, retarded fetal growth. Depression is also associated with premature birth. These data highlights the need for careful analysis and reevaluation of the risk-benefit ratio of initiating and maintaining use of psychoactive drugs during pregnancy (120).

A higher risk for persistent pulmonary hypertension (PPHn) in the newborn has been linked to the use of SSRIs like fluoxetine (Prozac) during the last trimester of pregnancy. Persistent pulmonary hypertension of the newborn is a cardiovascular condition usually seen within 12 hours of delivery.  When this happens, the infant’s pulmonary vascular resistance does not decrease as normally expected and blood is shunted away from the lungs.  This diversion results in an insufficiently oxygenated blood that causes respiratory distress in the infant, which may require assisted ventilation.  PPHM occurs in approximately 2 in 1000 births (127). 

Anxiety disorders can also be triggered or worsened by pregnancy.  Panic disorder, obsessive-compulsive disorder, and generalized anxiety disorder appear to be as common as depression. Fluoxetine (Prozac) is the most prescribed and thoroughly researched antidepressant in the United States.  There is a large pool of data collected from over 2500 cases that indicates no increase in risk of major congenital malformation in infants exposed to this drug.  Studies of other SSRI antidepressants show the same results, though these have not been backed by such large data. Older antidepressants such as MAOIs are generally not recommended during pregnancy because of their extensive dietary restriction requirements that can compromise the mother’s nutritional status, induce hypertension, and adversely react with terbutaline, a drug used to suppress premature labor (126).


Pediatric

Children are not untouched by mental illness. According to cumulative research data, 1 in 5 children and adolescents in the United States suffer from a behavioral or emotional disorder. ADHD, pediatric conduct disorder, depression, bipolar disorder, oppositional defiant disorder, mood disorders, obsessive-compulsive disorders, mixed manias, social phobia, anxiety, sleep disorders, borderline disorders, assorted “spectrum” disorders, irritability, aggression, pervasive development disorders, personality disorders, and there are others discussed in the pediatric psychiatry literature. The field of pediatric psychopharmacology is a rapidly growing area of care, and an indispensable part of pediatric psychiatric treatment (128).

Perhaps the greatest concern in the psychopharmacologic treatment of pediatric patients lies in the fact that there’s a huge potential for over diagnosis and overtreatment without adequate clinical data supporting the efficacy and safety of psychotropic agents in this particular population (129).

Below are the three main challenges in the provision of appropriate psychopharmacologic treatment to pediatric patients (130):



  1. Inadequate medication response: The lack of efficacy is one of the two most commonly cited reasons for nonadherence to pharmacotherapy.


  1. Significant adverse drug reactions: The second most commonly cited reason for noncompliance is the crippling side effects, disabling the child to function normally at school and among his peers. This is an important area of management wherein clinicians need to tread carefully because children may very well develop a negative view towards medication that may have proved helpful. Since many adult psychiatric disorders have an onset at an early age, a past error in psychopharmacologic treatment choices can spur a lifetime of consequences for the patient, the family and the present clinician.




  1. Lack of specialized child and adolescent psychiatrists (131): In the face of ongoing shortages of specialized child and adolescent psychiatrists, the responsibility of providing psychopharmacologic treatment often falls on adult psychiatrists, family physicians, and pediatricians.

Atypical antipsychotics

In 2007, risperidone received FDA approval for the treatment of schizophrenia in adolescents age 13 to 17 and single therapy in short-term treatment of manic or mixed episodes of bipolar I disorder in children and adolescents age 10 to 17. A study made recently suggests that this drug elevates prolactin levels in children age 7-17 treated with it. The implication of this finding is especially important for those children entering puberty as they may develop more than normal increase in breast size and galactorrhea (132).


Antidepressants

A is a rise in the research, current expert guidelines and consensus statements that back the efficacy of SSRIs and the tricyclic antidepressant (TCA), clomipramine (Anafranil), in the treatment of obsessive compulsive disorder (OCD) in psychiatric pediatric patients.

The use of sertraline (Zoloft), paroxetine (Paxil) and fluoxetine (Prozac) in pediatric patients show that they exhibit similar pharmacokinetic profiles as in adults. Although the half life of these drugs do tend to be shorter because of the more rapid metabolism and hepatic blood flow in children, the dosing schedules remain the same, i.e. fluoxetine and sertraline are given once a day and fluvoxamine twice a day when doses are above 100/mg day total. The slight difference in pharmacokinetic data does not have clinical significance in the overall pharmacodynamics of the drug (133).

A study found that a quarter of pediatric subjects treated with SSRIs and clomipramine exhibit agitation that could potentially cause mania and hypomania. The paradoxical effects warrant further investigation and careful monitoring since these drugs may very well induce the onset of another potentially serious mental illness, bipolar disorder (133).

Paroxetine has a short half-life and may cause withdrawal symptoms after as few as 6-8 weeks of treatment. Therefore, the FDA has recommended clinicians who prescribe it to closely monitor patients, with at least a weekly face to face follow up during the first 4 weeks of therapy and specific visit intervals thereafter (134).


It is the clinician’s responsibility to inform parents and patients about adverse effects, the dose, the timing of therapeutic effect, and the danger of overdose of the administered antidepressants, especially TCAs, prior to initiation of psychopharmacologic treatment. With TCAs, clinicians need to determine the exact dosage for patients because these drugs are known to cause fatal overdose at therapeutic dosages. On the other hand, parents need to take an active role in the drugs’ storage and administration, especially parents of younger children or children with suicidal tendencies (135).

The TCAs have been surpassed by the SSRIs when it comes to safety. As such, they are no longer the first line of drug for pediatric depression. Moreover, they require a baseline electrocardiogram (ECG), resting blood pressure, pulse, and weight monitoring prior to initiation of treatment. SSRIs have no such laboratory test prerequisites in healthy individuals (135). The risk of QT-prolongation is rare but nevertheless present in patients with risk factors for arrhythmias. These patients are best managed by another antidepressant.

Stimulants

More than 80% of stimulant medications use in the world occurs in the US. A study conducted in 2008 attributes this huge number to cultural influence on the identification and management of psychiatric disorders than any other field in medicine (136). 

At the heart of ADHD management is psychopharmacology, which consists of stimulants, norepinephrine reuptake inhibitors, alpha-2 agonists and antidepressants. Stimulants like amphetamine and methylphenidate (Ritalin) rank the best evidenced-based medications for improving attention dysfunction in children and adolescents.

The past 50 years have seen the development of various methylphenidate (MPH) formulations, ranging from sustained tablet (long acting) release to patches. A systematic review and meta-analysis conducted by Punja et al. found that long-acting MPH formulation have a little effect on the severity of inattention/overactivity and hyperactivity/impulsivity according to parent reports, whereas the short-acting formulation was preferred according to teacher reports for hyperactivity (137). Despite the long history of effectiveness, MPH type of medications comes with side effects that can discourage patients from following through with recommended drug regimen (see Table 18).


Medication

Side effects

Methylphenidate (MPH)

Addiction, insomnia, decreased appetite, agitation, headache, heart palpitations, loss of weight, dizziness, growth suppression (38).

Magnesium pemoline

Hepatic failure *

Dextroamphetamine

Depression, dysuria, bladder pain




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