Alastair J. Flint

Anhedonia and Reward-Circuit Connectivity Distinguish Nonresponders from Responders to Dorsomedial Prefrontal Repetitive Transcranial Magnetic Stimulation in Major Depression

BACKGROUND Depression is a heterogeneous mental illness. Neurostimulation treatments, by targeting specific nodes within the brains emotion-regulation network, may be useful both as therapies and as probes for identifying clinically relevant depression subtypes. METHODS Here, we applied 20 sessions of magnetic resonance imaging-guided repetitive transcranial magnetic stimulation (rTMS) to the dorsomedial prefrontal cortex in 47 unipolar or bipolar patients with a medication-resistant major depressive episode. RESULTS Treatment response was strongly bimodal, with individual patients showing either minimal or marked improvement. Compared with responders, nonresponders showed markedly higher baseline anhedonia symptomatology (including pessimism, loss of pleasure, and loss of interest in previously enjoyed activities) on item-by-item examination of Beck Depression Inventory-II and Quick Inventory of Depressive Symptomatology ratings. Congruently, on baseline functional magnetic resonance imaging, nonresponders showed significantly lower connectivity through a classical reward pathway comprising ventral tegmental area, striatum, and a region in ventromedial prefrontal cortex. Responders and nonresponders also showed opposite patterns of hemispheric lateralization in the connectivity of dorsomedial and dorsolateral regions to this same ventromedial region. CONCLUSIONS The results suggest distinct depression subtypes, one with preserved hedonic function and responsive to dorsomedial rTMS and another with disrupted hedonic function, abnormally lateralized connectivity through ventromedial prefrontal cortex, and unresponsive to dorsomedial rTMS. Future research directly comparing the effects of rTMS at different targets, guided by neuroimaging and clinical presentation, may clarify whether hedonia/reward circuit integrity is a reliable marker for optimizing rTMS target selection.

Anxious Depression in Elderly Patients: Response to Antidepressant Treatment

The authors asked whether elderly patients with anxious depression were less responsive to antidepressant treatment than nonanxious depressed patients. A group of 101 depressed patients were treated with 6 weeks of nortriptyline and then, if necessary, 2 weeks of adjunctive lithium. Patients who did not respond to or were intolerant of this first line of treatment were then given 6 weeks of phenelzine (+/- lithium augmentation). Finally, patients failing this second line of treatment were given either a course of electroconvulsive therapy or 6 weeks of fluoxetine (+/- lithium augmentation). Based on their score on the Hospital Anxiety and Depression Scale at index assessment, subjects were divided into anxious and nonanxious groups. Anxious depressed patients were significantly less responsive to nortriptyline on both intent-to-treat and efficacy analyses. They were also more likely to discontinue treatment and, as a result, were significantly less responsive on the intent-to-treat analysis for overall treatment. These results suggest that concurrent symptoms of anxiety have prognostic importance in geriatric depression.

Resting-State Cortico-Thalamic-Striatal Connectivity Predicts Response to Dorsomedial Prefrontal rTMS in Major Depressive Disorder

Despite its high toll on society, there has been little recent improvement in treatment efficacy for major depressive disorder (MDD). The identification of biological markers of successful treatment response may allow for more personalized and effective treatment. Here we investigate whether resting-state functional connectivity predicted response to treatment with repetitive transcranial magnetic stimulation (rTMS) to dorsomedial prefrontal cortex (dmPFC). Twenty-five individuals with treatment-refractory MDD underwent a 4-week course of dmPFC-rTMS. Before and after treatment, subjects received resting-state functional MRI scans and assessments of depressive symptoms using the Hamilton Depresssion Rating Scale (HAMD17). We found that higher baseline cortico-cortical connectivity (dmPFC-subgenual cingulate and subgenual cingulate to dorsolateral PFC) and lower cortico-thalamic, cortico-striatal, and cortico-limbic connectivity were associated with better treatment outcomes. We also investigated how changes in connectivity over the course of treatment related to improvements in HAMD17 scores. We found that successful treatment was associated with increased dmPFC-thalamic connectivity and decreased subgenual cingulate cortex-caudate connectivity, Our findings provide insight into which individuals might respond to rTMS treatment and the mechanisms through which these treatments work.

Affective correlates of fear of falling in elderly persons.

OBJECTIVE Fear of falling is common in older people, occurring on average in 50% of those who have fallen in the previous year. Little is known about the psychological correlates of fear of falling. The purpose of this study was to determine whether clinically significant depression and anxiety were independently associated with fear of falling. METHODS This was a cross-sectional study of 105 persons age > or =60 years, admitted to medical or orthopedic wards, who had fallen at least once in the previous 12 months. Fear of falling was assessed using two different constructs: 1) intensity of fear; and 2) self-efficacy. Depressive and anxiety disorders were assessed with the Structured Clinical Interview for DSM-IV. Depression and anxiety severity were assessed with the Hospital Anxiety and Depression Scale. Demographic, physical, functional, and social variables previously found to be associated with fear of falling were also measured. Logistic-regression and multiple-regression analyses were used to examine the independent association of affective variables with fear of falling. RESULTS Depressive disorders, anxiety disorders, depression severity, and anxiety severity had significant independent associations with both constructs of fear of falling. Of all the variables that were measured, depressive disorders and depression severity had the strongest associations with fear of falling. CONCLUSION Affective variables had a stronger association with fear of falling than non-affective variables in a hospital-based group of subjects. Further research is needed to determine whether similar findings occur in a community-based sample of older people.

A Double-blind Randomized Controlled Trial of Olanzapine Plus Sertraline vs Olanzapine Plus Placebo for Psychotic Depression: The Study of Pharmacotherapy of Psychotic Depression (STOP-PD)

CONTEXT Evidence for the efficacy of combination pharmacotherapy has been limited and without positive trials in geriatric patients with major depression (MD) with psychotic features. OBJECTIVES To compare remission rates of MD with psychotic features in those treated with a combination of atypical antipsychotic medication plus a serotonin reuptake inhibitor with those treated with antipsychotic monotherapy; and to compare response by age. DESIGN Twelve-week, double-blind, randomized, controlled trial. SETTING Clinical services of 4 academic sites. Patients Two hundred fifty-nine subjects with MD with psychotic features randomized by age (<60 or > or =60 years) (mean [standard deviation (SD)], 41.3 [10.8] years in 117 younger adults vs 71.7 [7.8] years in 142 geriatric participants). Intervention Target doses of 15 to 20 mg of olanzapine per day plus masked sertraline or placebo at 150 to 200 mg per day. Main Outcome Measure Remission rates of MD with psychotic features. RESULTS Treatment with olanzapine/sertraline was associated with higher remission rates during the trial than olanzapine/placebo (odds ratio [OR], 1.28; 95% confidence interval [CI], 1.12-1.47; P < .001); 41.9% of subjects who underwent combination therapy were in remission at their last assessment compared with 23.9% of subjects treated with monotherapy (chi(2)(1) = 9.53, P = .002). Combination therapy was comparably superior in both younger (OR, 1.25; 95% CI, 1.05-1.50; P = .02) and older (OR, 1.34; 95% CI, 1.09-1.66; P = .01) adults. Overall, tolerability was comparable across age groups. Both age groups had significant increases in cholesterol and triglyceride concentrations, but statistically significant increases in glucose occurred only in younger adults. Younger adults gained significantly more weight than older subjects (mean [SD], 6.5 [6.6] kg vs 3.3 [4.9] kg, P = .001). CONCLUSIONS Combination pharmacotherapy is efficacious for the treatment of MD with psychotic features. Future research must determine the benefits vs risks of continuing atypical antipsychotic medications beyond 12 weeks. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00056472.

Generalised anxiety disorder in elderly patients : epidemiology, diagnosis and treatment options.

Generalised anxiety disorder (GAD) is characterised by at least 6 months of excessive uncontrollable worry accompanied by symptoms of motor tension and vigilance and scanning. As with other anxiety disorders, GAD is less prevalent in older adults than younger adults. GAD has a high level of comorbidity with other psychiatric disorders and this has a bearing on estimates of its prevalence. GAD that is comorbid with another psychiatric disorder has a period prevalence of approximately 4% in community-dwelling older people. On the other hand, ‘pure’ GAD is less common, with a period prevalence of approximately 1%. Pure GAD in late life is a fairly even mix of chronic cases that began earlier in life and cases starting for the first time in later life.The most frequent and consistent finding regarding late-life generalised anxiety is its high level of comorbidity with major depression. There are few longitudinal data pertaining to the temporal association of generalised anxiety and major depression in late life, but the data that do exist suggest that the anxiety is frequently symptomatic of the depression. If generalised anxiety occurs exclusively during episodes of major depression, a separate diagnosis of GAD is not warranted.Cognitive behaviour therapy (CBT) is the most frequently studied psychological treatment for GAD. Although CBT is more effective than a wait-list control condition, it is not more effective than nondirective therapies in late-life GAD. Furthermore, a standard course of CBT appears to be less efficacious for GAD in older adults than younger adults. Further research is needed to develop more efficacious and specific forms of psychotherapy for late-life GAD.The three classes of medications that are most commonly used for GAD are: (i) antidepressants; (ii) benzodiazepines; and (iii) buspirone. Antidepressant medication is the pharmacological treatment of choice for most older adults with generalised anxiety. When generalised anxiety is secondary to an episode of major depression, the selection of an antidepressant is guided by the same principles that apply to treatment of nonanxious depression. Antidepressant medication is also effective for GAD in the absence of an episode of major depression. In this situation, citalopram and venlafaxine have been found to be efficacious in older people. Data from studies of mixed-aged patients suggest that escitalopram, paroxetine and trazodone may also be beneficial in late-life GAD. Despite their widespread use in older persons with anxiety, benzodiazepines have a limited role in the treatment of GAD in the elderly. If a benzodiazepine is initiated, pharmacokinetic considerations favour the use of either lorazepam or oxazepam. Buspirone also has a more limited role than antidepressants in the treatment of late-life GAD.

Pharmacotherapy of Bipolar Disorder in Old Age Review and Recommendations

The authors reviewed the evidence-base for pharmacological treatment of mania and bipolar (BP) depression in late life. Treatment benefits and side effects may be modified by age-associated factors, such as neurocognitive impairments. Lithium and divalproex have most often been studied in elderly patients, and both may be efficacious in acute treatment of mania, but there are no controlled efficacy or effectiveness trials. The role of atypical antipsychotic agents remains to be clarified. Similarly, there are no systematic studies of the treatment of BP depression in elderly patients. The authors make suggestions for management and delineate priorities for research.

Two-year outcome of elderly patients with anxious depression

The purpose of this study was to determine whether there was a difference in the long-term outcome between elderly patients with anxious depression and those with non-anxious depression. Eighty-three patients with non-bipolar, non-psychotic major depression who had responded to treatment of the index episode were maintained on full-dose antidepressant medication and followed on a monthly basis over a period of 2 years. Anxiety status at index assessment was not related to outcome as defined by rates of relapse and recurrence or time to these events. However, the few patients who remained anxious at the point of remission of the index episode had a significantly shorter time to relapse/recurrence. These findings suggest that, once they achieve remission and are given adequate prophylactic treatment, most older patients with anxious depression have a similar long-term outcome to patients without anxiety.

The complex interplay of depression and falls in older adults: a clinical review.

Depression and falls have a significant bidirectional relationship. Excessive fear of falling, which is frequently associated with depression, also increases the risk of falls. Both depression and fear of falling are associated with impairment of gait and balance, an association that is mediated through cognitive, sensory, and motor pathways. The management of depression in fall-prone individuals is challenging, since antidepressant medications can increase the risk of falls, selective serotonin reuptake inhibitors may increase the risk of fragility fractures, and data are lacking about the effect of fall rehabilitation programs on clinically significant depression. Based on the current state of knowledge, exercise (particularly Tai Chi) and cognitive-behavioral therapy should be considered for the first-line treatment of mild depression in older fallers. Antidepressant medications are indicated to treat moderate to severe depression in fall-prone individuals, but with appropriate precautions including low starting dose and slow dose titration, use of psychotropic monotherapy whenever possible, and monitoring for orthostatic hypotension and hyponatremia. To date, there have been no recommendations for osteoporosis monitoring and treatment in individuals prescribed antidepressant medications, beyond the usual clinical guidelines. However, treatment of the older depressed person who is at risk of falls provides the opportunity to inquire about his or her adherence with osteoporosis and fracture prevention guidelines.

The effect of sequential antidepressant treatment on geriatric depression

This study evaluated the outcome of elderly depressed patients who were refractory to, or intolerant of, an initial trial of nortriptyline and who then underwent systematic treatment with other antidepressant therapies. 101 patients entered the study and 61% responded to nortriptyline, 64% of patients who did not improve with nortriptyline eventually responded to other antidepressant treatments. Response to second-line treatment (phenelzine) was significantly slower than response to the tricyclic antidepressant. Treatment nonresponders were more likely to have a longer episode length at index assessment and higher baseline anxiety scores compared with responders. This study demonstrates the importance of persisting with systematic antidepressant therapy in elderly patients who do not respond to the first trial of treatment.