Although most patients with depression ultimately respond to antidepressant therapy, >50% have inadequate response to an individual antidepressant trial. The desire to avoid adverse drug reactions is common among patients, and is an important determinant of drug selection among psychiatrists. However, since the major classes of antidepressants and antipsychotics appear to be comparable in efficacy, clinicians have little basis for selecting the most effective agent for an individual patient. Pharmacogenetics, often described as the study of genetic variation that explains differential response to medication, represents an important new avenue toward improving treatment outcomes. Genetic variation in drug-metabolizing enzymes has been recognized for decades. The main focus of current psychiatric pharmacogenetic testing is on the cytochrome P450 (CYP) 2D6 and, to a somewhat lesser extent, on the 2C19 genes. Data suggest that poor metabolizer status can be associated with an increased risk of adverse drug reactions with certain medications, and that ultra-rapid metabolizers may require higher-than-usual doses to achieve a therapeutic response. The importance of CYP enzymes in the metabolism of several antidepressant and antipsychotic drugs suggest that genetic variation may aid in medication selection or dosing. Advances in pharmacogenetic research may facilitate the development of personalized medicine in which genetic information can inform drug selection, leading to optimal drug effectiveness and minimal drug toxicity.

In this monograph, David A. Mrazek, MD, provides an overview of the context of genetic testing in clinical psychiatric practice. Next, Jordan W. Smoller, MD, ScD, discusses some of the practical issues related to medication selection. Finally, Jose de Leon, MD, presents a comprehensive review of antidepressant and antipsychotic treatment based on drug metabolism, and reviews the available testing methods for CYP 2D6 and 2C19 genotypes.

A significant proportion of depressed patients will experience multiple episodes of depression throughout their lifetimes, and, in recent years, attention has been paid to the identification of risk factors associated with a recurrent course of major depression. Residual depressive symptoms following acute phase therapy appears to be the most important clinical risk factor leading to recurrence. However, advances in empirically-supported treatment algorithms and guidelines, and in pharmacotherapy and psychotherapy, provide physicians with the tools necessary to improve short- and long-term outcomes in the treatment of depression. Additionally, recent developments in genetic and psychological vulnerability research have sought to further improve outcomes by identifying markers in patients who may likely experience multiple depressive episodes.

The presentations and clinical courses of patients with bipolar disorder differ greatly by gender. In addition, medical therapy must be tailored differently for men and women because of emerging safety concerns unique to the female reproductive system. In November 2005, these topics were explored by a panel of experts in psychiatry, neurology, and reproductive health at a closed roundtable meeting in Dallas, Texas. This clinical information monograph summarizes the highlights of that meeting.

Compared to men with bipolar disorder, women have more pervasive depressive symptoms and experience more major depressive episodes. They are also at higher risk for obesity and certain other medical and psychiatric comorbidities. Mood changes across the menstrual cycle are common, although the severity, timing, and type of changes are variable. Bipolar disorder is frequently associated with menstrual abnormalities and ovarian dysfunction, including polycystic ovarian syndrome. Although some cases of menstrual disturbance precede the treatment of bipolar disorder, it is possible that valproate and/or antipsychotic treatment may play a contributory role in young women.

Pregnancy does not protect against mood episodes in untreated women. Maintenance of euthymia during pregnancy is critical because relapse during this period strongly predicts a difficult postpartum course. Suspending therapy in the first months of pregnancy may be an option for some women with mild-to-moderate illness, or those with a long history of euthymia during pre-pregnancy treatment. However, a mood stabilizer should be reintroduced either in the later stages of pregnancy or in the immediate postpartum period. Preliminary data suggest that fetal exposure to some mood stabilizers may raise the risk of major congenital malformations and neurodevelopmental delays. For women planning to become pregnant, clinicians may consider switching to other drugs before conception. The value and drawbacks of breastfeeding during treatment must be considered in partnership with the patient, with close monitoring of nursing infants thereafter. The risks and benefits of medical treatment for women with bipolar disorder should be carefully reconsidered at each stage of their reproductive lives, with a flexible approach that is responsive to the changing needs of patients and their families.

Depression is a chronic illness whose true costs to society are unclear. The costs associated with depression are direct (drugs and treatment), indirect (absenteeism and loss of productivity), and intangible (quality of life). Direct costs are usually easy to quantify. Indirect costs often test the ingenuity of researchers whose results are, at best, crude approximations. Intangible costs are elusive and may never be measured with any degree of accuracy. To compound matters further, many patients with depression have never been diagnosed, which complicates the cost accounting analysis of depression from a societal perspective. What is clear is that the worldwide costs of depression are climbing The overall costs of treating depression attributable to drug therapy are modest. The appropriate choice of antidepressant therapy is likely to be the product that provides the highest effectiveness in terms of overall costs. As a result, it is important that prescribers have an idea of the benefit derived from the cost of drugs, and how the cost effectiveness of different drugs compare.

Previous studies of antidepressant cost effectiveness have suggested that the use of venlafaxine, which costs more than generic selective serotonin reuptake inhibitors (SSRIs), may be no more costly when total costs (eg, how many drugs were prescribed, how many medical or emergency room visits patients had, and how often they were hospitalized) are calculated. The objectives of this retrospective, populationbased, database study were to identify patient characteristics and factors associated with the choice of antidepressant in order to assess differences in persistence, healthcare utilization, and direct medical costs associated with venlafaxine and SSRI pharmacotherapy.

Study results indicated that in this real-world setting, medical costs were similar among depressive patients treated with venlafaxine and SSRIs. The higher purchase price of venlafaxine was balanced by cost savings due to fewer hospitalizations and fewer outpatient medical visits. Differences in drug treatment may also partially explicate the observed differences in average direct medical costs between venlafaxine and SSRIs.

Although most patients with depression ultimately respond to antidepressant therapy, >50% have inadequate response to an individual antidepressant trial. The desire to avoid adverse drug reactions is common among patients, and is an important determinant of drug selection among psychiatrists. However, since the major classes of antidepressants and antipsychotics appear to be comparable in efficacy, clinicians have little basis for selecting the most effective agent for an individual patient. Pharmacogenetics, often described as the study of genetic variation that explains differential response to medication, represents an important new avenue toward improving treatment outcomes. Genetic variation in drug-metabolizing enzymes has been recognized for decades. The main focus of current psychiatric pharmacogenetic testing is on the cytochrome P450 (CYP) 2D6 and, to a somewhat lesser extent, on the 2C19 genes. Data suggest that poor metabolizer status can be associated with an increased risk of adverse drug reactions with certain medications, and that ultra-rapid metabolizers may require higher-than-usual doses to achieve a therapeutic response. The importance of CYP enzymes in the metabolism of several antidepressant and antipsychotic drugs suggest that genetic variation may aid in medication selection or dosing. Advances in pharmacogenetic research may facilitate the development of personalized medicine in which genetic information can inform drug selection, leading to optimal drug effectiveness and minimal drug toxicity.

In this monograph, David A. Mrazek, MD, provides an overview of the context of genetic testing in clinical psychiatric practice. Next, Jordan W. Smoller, MD, ScD, discusses some of the practical issues related to medication selection. Finally, Jose de Leon, MD, presents a comprehensive review of antidepressant and antipsychotic treatment based on drug metabolism, and reviews the available testing methods for CYP 2D6 and 2C19 genotypes.

We present a case of psychotherapy where a process of forgiveness occurs. Then we review the relevant cognitive-affective neuroscience and clinical implications. Resentment and forgiveness emerge within particular kinds of social interactions and can now increasingly also be conceptualized as embodied in particular neurocircuitry. There may be an association between increased psychopathology and decreased forgiveness, and the implications of this for assessment and treatment deserve further study. There may be gender differences in forgiveness; a highly speculative hypothesis suggests that these would reflect sexual divergence in the evolutionary origins of reconciliatory behavior.

A 14-year-old girl with anorexia nervosa (AN) was found to have an intracranial neoplasm. Atypical psychological symptoms prompted further evaluation, including electroencephalogram and neuroimaging, which revealed a sellar and suprasellar mass.This patient had an eating disorder and a brain tumor, which appear to be two unrelated conditions. However, it remains unclear how each affected the other. The diagnosis of AN, like all other psychiatric disorders, requires that possible medical etiologies and coexisting medical problems be excluded. AN and other eating disorders are particularly difficult to diagnose in children and adolescents because they often do not present in the manner typical of adults. Perceptual and cognitive disturbances associated with AN are difficult to evaluate because children and adolescents normally change over time as they progress through different stages of development. Therefore, It is particularly important to evaluate for the presence of medical conditions when a diagnosis of an eating disorder is made in a child or adolescent.

We describe a retrospective case series of three patients, two with bipolar depression and one with unipolar depression. Pramipexole is a Food and Drug Administration-approved antiparkinsonian agent, which, when used to augment antidepressants, would be considered an off-label use and should be discussed with the patient. These patients had robust responses to pramipexole augmentation of their treatment regimen. All three patients had been taking an atypical antipsychotic. The depressive symptoms were evaluated using the Hamilton Rating Scale for Depression.

Behavioral phenotypes are generally complex, reflecting the action of multiple different genes. Nevertheless, there is growing evidence that key gene variants can alter activity within specific neuronal circuits and, therefore, influence particular cognitive-affective phenomena. One example is the catechol-O-methyltransferase (COMT) gene, which has a common variant at codon 158. Those with valine (Val158) alleles have increased greater COMT activity and lower prefrontal extracellular dopamine compared with those with the methionine (Met158) substitution. Val158 alleles may be associated with an advantage in the processing of aversive stimuli (warrior strategy), while Met158 alleles may be associated with an advantage in memory and attention tasks (worrier strategy). Under conditions of increased dopamine release (eg, stress), individuals with Val158 alleles may have improved dopaminergic transmission and better performance. while individuals with Met158 alleles may have less efficient neurotransmission and worse performance. Some evidence suggests that Val158 alleles are associated with schizophrenia, while Met158 alleles are associated with anxiety.

Depression is increasingly recognized as a highly recurrent and potentially chronic illness that imposes a substantial burden on individuals, families, and society. Evidence indicates that the risks of depressive recurrence, treatment resistance, and chronicity increase as the illness becomes more highly recurrent. Up to 1 year of continuation phase therapy is now recommended for virtually all depressed patients who respond to antidepressants, with a longer course of maintenance phase pharmacotherapy recommended for those who have experienced multiple episodes. Antidepressants, when effective during the acute phase of therapy, reduce the risk of depressive relapse (continuation phase) and recurrence (maintenance phase) by at least 50%. Longer-term antidepressant pharmacotherapy is most effective when the full dose of medication effective during acute-phase treatment is continued. As combined treatment with antidepressants and psychotherapy may improve shorter-term outcomes for patients with more severe recurrent depression, ongoing combined therapy may be indicated, especially for patients at particularly high risk. Approximately 5% to 10% of patients maintained on antidepressants relapse yearly, leading some to implicate tachyphylaxis. However, before attributing relapse or recurrence to diminished responsiveness to antidepressant medication at the neurochemical level, clinicians should ensure that the patient has been adherent to therapy as prescribed and consider other explanations.

Anxiety and depression are common disorders that frequently co-exist. Both disorders show good response to antidepressants, especially the selective serotonin reuptake inhibitors. Some suggest that these disorders are variants of the same underlying brain pathology. This review examines the similarities and differences between anxiety and depression in terms of the known neurobiological etiologic mechanisms as well as their biological underpinnings and response to treatment. Sufficient and significant differences between these disorders support the view that they are independent entities. Shared abnormalities in the 5HT1A receptor function, for example, may help explain some of the comorbidity.

Although there is a wide array of choices of antidepressants, there is little empirical evidence to guide clinicians in their selection. Most reviews of the antidepressant literature, including the American Psychiatric Association's (APA) Practice Guideline for the Treatment of Major Depressive Disorder, conclude that these medications are generally equally effective. Consistent with this, a recent metaanalysis of studies comparing two or more new-generation antidepressants found little evidence that any medication was superior to the others. Although the APA guideline suggests that the choice of antidepressant be based principally on side effects, tolerability, patient preference, and cost, it also reviewed evidence of differential treatment response related to patients' clinical profiles. For patients with nonpsychotic, nonbipolar major depressive disorder (MDD), the guideline indicated that the presence of anxiety symptoms, atypical features, melancholic subtype, symptom severity, and borderline personality disorder may be associated with differential response to antidepressants. Selective serotonin reuptake inhibitors (SSRIs) are recommended for high anxiety, SSRIs and clomipramine for obsessive-compulsive disorder (OCD) symptoms, tricyclic antidepressants (TCAs) for severe depression and melancholia, and SSRIs and monoamine oxidase inhibitors (MAOIs) for atypical depression.

What is most striking in the guideline's review is how limited in scope and utility are the data to guide the outpatient psychiatrist in selecting an antidepressant. Melancholia and severe depression are relatively infrequently encountered in the outpatient setting. The most common comorbidities in depressed outpatients are anxiety disorders, but the guideline simply says that bupropion may be anxiogenic and should be avoided, and that although MAOIs may work well in depressed patients with anxiety, other medications are preferred. It does not discuss the possible influence of specific comorbidities on antidepressant selection.

Introduction: The aim of this study was to compare the level of insight in patients with body dysmorphic disorder (BDD) with and without comorbid obsessive-compulsive disorder (OCD), and to measure its possible relationships with clinical features.

Methods: Thirty outpatients affected by BDD, according to Diagnostic and Statistical Manual of Mental Disorder, Fourth Edition criteria, of whom 18 were also suffering from OCD, were included in the study. Clinical assessment was carried out by means of the Yale-Brown Obsessive-Compulsive Scale modified for BDD and a specially designed OCD Questionnaire. The level of insight was measured by means of the score at item 11 of the Yale-Brown Obsessive-Compulsive Scale modified for BDD.

Results: The insight resulted to be excellent in four cases, good in four, fair in five, poor in 15 and absent in two. Significant and positive correlations were observed between the level of insight and the following items: resistance to thoughts and to activities as well as to time spent on activities and control on activities related to the defect. The insight was significantly lower in patients affected by both BDD and OCD.

Conclusion: The findings indicate that the majority of BDD patients in this study, and especially those with comorbid OCD, have a low degree of insight that is significantly correlated to symptoms specific of the disorder.