Reduction of blood platelet serotonin levels in manic and depressed patients.

Blood platelet serotonin levels were measured in unmedicated 12 manic and 74 depressive patients with 118 normal control subjects employed. Blood platelets were separated by multiple centrifugation in the medium of Na2-EDTA solution, and the loss of serotonin during collecting procedures was about 11%. The mean value of blood platelet serotonin levels in depressed patients was 594 +/- 288 ng/mg platelet protein (+/- S.D.), which was significantly lower than that for normal controls, 780 +/- 253 ng/mg protein (p less than 0.001). Age does not account for the reduction of serotonin levels both in depressed and in normal population. Unipolar and involutional depressed patients exhibited to have the most pronounced reduced levels of serotonin of various subtypes of depression, while bipolar depressed patients, neurotic and chronic characterological depressed patients as well as patients with first-episode depression had the values which were comparable with those in normal controls. Manic patients did not show enhancement but did reduction of serotonin levels, the mean being 580 +/- 152 ng/mg protein, which made a contrast with their clinical manifestations of exhilaration and hyperactivity. Changes in blood platelet serotonin levels were determined before, during and after administration of L-5-HTP with a maintenance dose of 300 mg daily in nine depressed patients. Serotonin levels in all subjects were lifted to normal levels during the L-5-HTP treatment, while clinical symptoms were not improved with the treatment. Reduction of blood platelet serotonin levels in depressed patients may be due to their psychobiological distinction, which involves abnormal biogenic amine metabolism in the brain.     

Monoamine Oxidase Activity in Blood Platelets From Manic and Depressed Patients

To evaluate the possible abnormality in MAO activity in affective disorders, blood platelet samples were obtained from 80 patients with mania and depression. Blood-platelet MAO activity was measured by a newly developed assay procedures using serotonin as substrate. MAO activities in 121 normal adult subjects were in a range of 2.49-12.05 nM/mg protein/hour, with the mean values of 4.91 ±1.72 (±S.D.) for men and 6.88±1.99 for women. (p<0.001) MAO activities in the manic and depressed patients were in a range of 0.65–13.40 nM/mg protein/hour, and both manic and depressed patients showed the mean value very similar to that in the normal subjects. Bipolar depressed patients did not exhibited lower MAO activity in the blood platelets than other clinical subtypes of depressive illness, including unipolar, involutional, neurotic and chronic characterological, and first-episode depressions. No significant differences were established between these five subcategories of depression, while significant higher values were evident in female than male patients (p<0.001). No correlation was found between the MAO activity and serotonin levels in the blood platelets either in the normal subjects or in the depressed patients.     

Measurement of 5–Hydroxyindole Compounds During L-5–HTP Treatment in Depressed Patients

L-5–hydroxytryptophan (L-5–HTP), an immediate serotonin precursor, was given to the hospitalized depressed patients in an open clinical trial of the Phase 2 study for an-tidepressive effects of the agent. A relatively small dose, 150 mg orally for seven days, was employed, and seven of 14 patients responded to the treatment with mild or moderate amelioration of their depressive symptoms. Urinary excretion levels and plasma concentrations of three 5–hydroxyindole compounds, 5–HTP, 5–HT and 5–HIAA, were measured during the drug treatment. Approximately 70% of the orally administered dose of L-5–HTP was recovered from the urine of depressed patients. Major part of urinary indoleamine metabolites was free and conjugate 5–HIAA. Excretion levels of these compounds in urine were not consistently altered in the depressed patients as compared to those in normal subjects. Clinical response to L-5–HTP treatment appeared to have some correlation with the biochemical measures in the depressed patients, that is, non-responders exhibited significantly lower excretion levels of 5–HT and 5–HIAA in urine, and lower plasma levels of 5–HT than responders. Administered L-5–HTP may not be fully utilized in the depressed patients who did not react to the agent.     

Growth Hormone Responses to Administration of L-5-Hydroxytryptophan (L-5-HTP) in Manic-Depressive Psychoses

Fourteen hospitalized patients with manic-depressive psychoses received L-5-hydroxy-tryptophan (L-5-HTP), a serotonin precursor, which has been postulated as a potent antidepressive agent. Plasma human growth hormone (HGH) and glucose levels were measured at 30 minute intervals after oral administration of 200mg of L-5-HTP. Plasma cortisol levels prior to L-5-HTP administration were also measured. 1. In five manic-depressive (bipolar) patients, aged 17 to 60, each subject studied in manic state showed an adequate HGH response of more than 5.0ng/ml (maximum levels:17.7±7.1 ng/ml Mean± S.E.M., controls, aged 27 to 41:10.5±1.6 ng/ml), while those in depressive state failed to secrete HGH adequately (maximum levels ranged 1.4-4.8 ng/ml) (p>0.05). 2. Of five determinations from three endogenous depressive (unipolar) patients, aged 30 to 51, three showed adequate responses (maximum levels ranged 2.6–16.5 ng/ml). Nine out of 10 tests from six patients with protracted depressive symptoms prolonged for 2 to 6 years, aged 45 to 65, had deficient responses of HGH (maxi mum levels: 2.1±k0.5 ng/ml Mean±S.E.M., ranged 0.1–5.6 ng/ml) (p>0.01). 3. Deficiency of pituitary HGH secretion appeared to correlate neither with the score of Hamilton's Depression Scale nor with the global judgement on the severity of the illness. Increments in the blood glucose levels after L-5-HTP administration were only mild ones, to which HGH insensitivity may be irrelevant. Morning plasma cortisol levels in depressives, ob served as high as those in manics, also may be unrelated. 4. Treatment with 300 mg of L-5HTP daily for two weeks proved to have no favorable clinical effects on four depressive patients, who were categorized as non-responders of HGH. Because there is evidence suggesting pituitary hormone release related to brain bio-genic amines, the deficient HGH responses to L-5-HTP in depressed patients may be due to a neurochemical defect hypothesized in the manic-depressive psychoses. The HGH responses were most distinctly diminished in the protracted depressive patients, suggesting an endocrine hypofunction which may cause the fixation of the depressive symptoms.     

THE LEVEL AND DIURNAL RHYTHM OF SERUM SEROTONIN IN MANIC-DEPPESSIVE PATIENTS

The serum levels and diurnal rhythm of serotonin before and during treatment were investigated in 65 manic-depressive patients, comparing with those in 34 normal controls and 13 schizophrenics. 1. The serum serotonin level in 40 newly admitted depressive patients who had not been medicated (127±58 ng/ml) was significantly lower than that in normal controls (221±96ng/ml). 2. The serum serotonin level in 24 recovering patients with depression had the tendency to return to normal while under treatment with imipramine type antidepressants (281±189 ng/ml). 3. The serum serotonin level in 10 manic patients (365±85 ng/ml) was significantly higher than that in normal controls. 4. After the injection of imipramine to depressive patients, serum serotonin level tended to increase (1.5 times). 5. Electroconvulsive shock did not appear to alter the serum serotonin level in depressive patients and normal dogs. 6. As for the diurnal rhythm of serum serotonin of depressive patients, the serotonin level in the morning was the lowest, which seemed to be related to the worst depressed mood in the morning. In the manic patients, the serotonin level at 20.00 hours was the highest. This pattern of rhythm resembled that of normal controls. 7. The significance of serum serotonin levels in manic-depressive patients was discussed.     

Reassessment of elevated serotonin levels in blood platelets in early infantile autism

Blood platelet serotonin content was measured in 30 children with early infantile autism, as defined by Kanner, 30 age-matched normal subjects, and 45 children with various neurological and psychiatric disorders. Serotonin content in the autistic group was 980±357 ng/mg platelet protein (mean±standard deviation), a value significantly higher than that for normal children, 807±202 ng/mg (p <.025). Autistic children under school age had higher platelet serotonin concentrations than other older autistic individuals. There was little correlation between age and serotonin levels in the normal children. Elevated serotonin was also seen in some of the non-autistic pathological group, who were disturbed and hyperactive. Elevated serotonin levels are not necessarily a specific biochemical finding for autistic children, but seem to be due to their behavioral distinction.     

Fluoxetine in the treatment of intention myoclonus

Some types of intention myoclonus respond to serotonin precursor therapy (e.g., L-5-hydroxytryptophan, L-5HTP). Fluoxetine, a specific serotonin (5HT) uptake blocker, was found to have no antimyoclonic effect when administered by itself to four patients with intention myoclonus. However, in two patients with intention myoclonus responsive to L-5HTP and carbidopa, fluoxetine reduced the required dose of L-5HTP to approximately one-third, with greater antimyoclonic activity, decreased side effects, and reduction in platelet 5HT and plasma 5-hydroxyindoleacetic acid and L-5HTP concentrations. These findings further support the hypothesis that some forms of intention myoclonus are caused by a deficiency of brain 5HT, and suggest that the addition of fluoxetine to L-5HTP and carbidopa may improve antimyoclonic therapy.     

Behavioral, neuroendocrine, and biochemical effects of 5-hydroxytryptophan administration in panic disorder

L-5-Hydroxytryptophan (5HTP) was administered to 20 patients suffering from panic disorder and to 20 healthy controls. Subjects received 60 mg 5HTP in 300 ml saline solution. Before, during, and up to 2 hours after 5HTP administration, symptoms of anxiety and depression were assessed. In addition, plasma 5HTP, 3-methoxy-4-hydroxyethylglycol (MHPG), cortisol, beta-endorphin, and melatonin levels were measured at several time points, and the kinetics of 5-hydroxytryptamine (5HT) in blood platelets were measured. During and after the infusion of 5HTP, none of the patients showed an increase in anxiety or depressive symptoms, despite the presence of severe side effects. Some patients even experienced the 5HTP infusion as a relief. In contrast to the patients, nine control subjects reported depressed mood, although no increases in anxiety were noted. In both patients and controls, the 5HTP infusion led to substantial increases in plasma cortisol and beta-endorphin levels, while the plasma MHPG level was unchanged. Plasma melatonin increased significantly after 5HTP administration, suggesting that increasing 5HT availability in man might affect melatonin synthesis. The results of this study are at odds with the hypothesis that there is a supersensitivity of 5HT2 receptors in panic disorder.     

Platelet and whole blood serotonin content in depressed inpatients: correlations with acute and life-time psychopathology.

Platelet or whole blood serotonin content did not differ significantly in patients with major depression compared to healthy controls, but within the patient group, platelet serotonin levels correlated negatively with severity of depression (r = -0.49, p = 0.007). Levels were 39% lower in patients who had made a suicide attempt compared to nonattempter patients (47.2 +/- 27.3 versus 77.6 +/- 41.7 ng/10(8) platelets, p = 0.04). Conversely, comorbid borderline personality disorder (85.3 +/- 41.5 ng/10(8) platelets) was associated with 31% greater platelet serotonin content than nonborderline patients (58.9 +/- 31.1 ng/10(8) platelets) and 27% greater than healthy controls (62.4 +/- 19.8 ng/10(8) platelets). A pronounced seasonal variation in whole blood and platelet serotonin content was found in both patients and controls, largely due to lower levels in summer. Excluding cases tested in the summer abolished the statistically significant differences in patients with and without comorbid borderline personality disorder (BPD). Nevertheless, BPD attempters had lower serotonin levels than BPD nonattempters but higher serotonin levels than non-BPD attempters. Current hostility and a life-time history of aggression were positively correlated with platelet serotonin content (r = 0.44, p = 0.04 and r = 0.41, p = 0.06). This study provides evidence for an association between lower platelet serotonin content and depression and suicidal behavior, and association of higher platelet serotonin content and comorbid borderline personality disorder and behavior traits such as aggressivity.     

Monoamine Oxidase Activity in Blood-Platelets From Autistic Children

In order to evaluate the possible abnormality in monoamine oxidase (MAO) activity in early infantile autism, blood platelet samples were obtained from 20 autistic children, aged 2–12 years. MAO activity, measured fluorometrically using serotonin as substrate, was 5.24 ± 1.65 (Mean ± Standard Deviation) nM/mg protein/hour in these autistic children. This value was not significantly different from either that in 30 age-matched normal children or that in 39 nonautistic children with various psychiatric and neurological disorders, although autistic children had higher platelet serotonin concentrations than these nonautistic individuals.     

Platelet MAO deamination of serotonin in depressed patients. Changes after imipramine treatment and clinical correlations

Monoamine oxidase (MAO) in blood platelets has been used as a model to study MAO in the central nervous system, where disorders in serotonergic systems are thought to occur in depression. Inconsistent changes in platelet MAO of depressed patients have been reported when several substrates other than serotonin (5-HT) have been used. To correlate changes in platelet MAO activity with the enzyme activity in central serotonergic systems, the platelet MAO activity of depressed patients (first unmedicated and then after 3 weeks and 2 months of imipramine treatment) and normal controls was measured using 5-HT as substrate. The results showed that there is a steady, measurable platelet MAO activity with that substrate. This activity was significantly higher in unmedicated depressed patients than in controls, and it decreased progressively with imipramine treatment, reaching a normal level when the patients were clinically recovered from depression after 2 months of therapy.     

The influence of selective serotonin reuptake inhibitors on human platelet serotonin

Clinical depression has been proposed to be an independent risk factor for cardiovascular disease. While it is suggested that selective serotonin reuptake inhibitors (SSRIs) reduce the risk of acute cardiovascular problems of depressed patients, the effect of SSRIs on platelets, the only blood cells committed to serotonin (5-HT) transport, remains largely unknown.The goal of this pilot study was to measure the 5-HT levels in platelets of untreated and SSRI-treated depressed patients and normal subjects and to determine whether the interaction of SSRIs with platelets can explain their possible cardiovascular benefit in patients with depression. Platelet 5-HT was determined by an immunocytochemical assay and high-pressure liquid chromatography with electrochemical detection (HPLC-ECD). In normal control subjects without cardiovascular disease, 78 +/- 8% of platelets were 5-HT-positive (n = 14). Depression caused a significant reduction in platelet 5-HT to 46 +/- 21% in untreated patients (n = 13) and 22 +/- 13% in SSRI-treated patients (n = 14). As a class, all selective serotonin reuptake inhibitors significantly reduced the 5-HT concentration in patient platelets. An inverse relationship of 5-HT level and dose of medication might be suggested.These results correlated well with 5-HT data from HPLC (r = 0.8509, p < 0.001). SSRIs did not affect platelet aggregation and dense granule release in response to thrombin, but significantly reduced ADP-induced platelet aggregation and dense granule release in both patient and normal control samples. The active inhibition of platelet aggregation by SSRIs might explain their cardiovascular benefit.     

Elevated P-selectin on platelets in depression: response to bupropion

Increased platelet activation has been suggested as a possible reason for the increased vulnerability of depressed patients to ischemic heart disease (IHD). Translocation of p-selectin, an integral -granule membrane protein, to the platelet surface is a measure of platelet activation. Herein, western blots of platelet plasma membranes containing p-selectin were quantified in patients with major depression (n=19; mean AGE=39 ± 2 years) and healthy comparison subjects (n=17; mean AGE=36 ± 2 years). None evidenced clinical signs of IHD, and only two patients had a lifestyle IHD risk factor (smoking). Blood was obtained from all 19 depressed patients before treatment, and 15 returned after 6–8 weeks of open-label bupropion treatment. Bupropion was chosen as the antidepressant because it did not elevate plasma norepinephrine or serotonin, endogenous agonists that can induce platelet degranulation. Western blotting revealed more p-selectin immunoreactivity (75 kD band) in depressed patients compared to healthy controls (P=0.003). After bupropion treatment, p-selectin remained high in depressed patients. β3-Integrin, a reference plasma membrane protein that does not translocate during activation, was of equivalent density in depressed patients and healthy control subjects, and was unchanged after treatment with bupropion. p-Selectin failed to correlate with severity of illness based on the Hamilton Depression scale, or with the post-treatment plasma concentration of bupropion. The results suggest an elevation in p-selectin on platelet plasma membranes might be a trait marker for depression.     

Platelet serotonin levels support depression scores for women with postpartum depression

OBJECTIVE: It is very challenging to make an unbiased diagnosis of psychiatric illness. Platelets have long been proposed as easily obtainable, neurological models of serotonergic neurons. This study examined whether a new measurement for platelet serotonin could aid in the diagnosis of postpartum depression and support the results from questionnaires. METHODS: Study participants included 11 patients with postpartum clinical depression according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, criteria. Blood was donated either at acute onset of depression before treatment (n = 5) or while patients were nonresponsive to paroxetine treatment (n = 8; 2 of these patients dropped out). A follow-up sample was donated approximately 8 weeks later during paroxetine treatment (n = 11). Platelet serotonin was determined with a new immunocytochemical assay and standard high-pressure liquid chromatography. Serotonin levels were compared with Hamilton Depression Rating Scale scores. RESULTS: Platelet serotonin levels in patients with depression before paroxetine treatment or nonresponsive to their initial paroxetine regimen were reduced to 50% of normal levels. Treatment-induced severe reduction of platelet-associated serotonin only occurred in responsive patients. Mean platelet serotonin levels were significantly lower in responders (17.3%, standard deviation [SD] 4%), compared with nonresponders (33.4%, SD 8%; p < 0.001). CONCLUSION: Platelet serotonin levels obtained with a new immunocytochemical test correlated well with results from depression scoring and might be useful as evidence-based support for questionnaires.     

Comparison of plasma cortisol and corticosterone in the dexamethasone suppression test for melancholia

The suppression of plasma corticosterone (B), measured by radioimmunoassay (RIA), was compared to simultaneous suppression of plasma cortisol (F), measured as total corticoids by a competitive protein binding (CPB) assay, in the overnight dexamethasone suppression test (DST). Baseline plasma B concentrations in IO control subjects were 4.04 ± 1.07 ng/ml (X ± S.D.) at 0800 hr and 1.51 ± 0.68 ng/ml at 1600 hr. Post-dexamethasone 1600 hr B levels in the controls were 0.46 ± 0.29 ng/ml. An early escape of plasma B (> 1.2 ng/ml), like that of F (> 5 μg/dl), during the overnight 24 hr 1.0 mg dose DST was noted in patients with melancholia (endogenous depression).Half-hourly catheter samples in a normal subject stimulated to escape from dexamethasone suppression showed that in general, plasma B concentrations parallel plasma F concentrations over a 12 hr period. Repeated weekly DSTs on two patients with different psychiatric diagnoses resulted in B: F correlations of 0.74 and 0.60. Overall agreement between B- and F-DST outcomes in all categories tested at 1600 and 2300 hr was 93%; the agreement in the melancholic and non-endogenous depressed groups was 100%.Post-dexamethasone, both B and F were suppressed 55–60% below the criterion level in controls. In those patients who escaped from dexamethasone suppression, the percentage increase in plasma B above the criterion level was significantly greater (+ 55%) than the corresponding percentage change in plasma F. Most patients with borderline abnormal F-DSTs (3.5–4.9 μg/dl) exhibited clearly abnormal B-DSTs (> 1.2 ng/ml). We conclude that the use of dexamethasone suppression of plasma B (using 1.2 ng/ml as the abnormal criterion value) is an additional indicator of an abnormal DST in depressed patients.     

Suicidal behavior in depression: relationship to platelet serotonin transporter

OBJECTIVE: Suicidal behavior in depressed patients is associated with low central serotonin. Thus, platelet serotonin uptake in relation to suicidal behavior in depression was examined. METHODS: Depressed patients who had never attempted suicide (n = 23) were compared with depressed patients who had never attempted suicide (n = 26) and normal controls (n = 71) for platelet serotonin uptake. RESULTS: Depressed patients who had a lifetime history of a suicide attempt had a significantly greater apparent Michaelis constant (Km) of platelet serotonin uptake than either depressed patients who had never attempted suicide or controls. Patients rated high for current suicidal ideation at the index admission had significantly higher Km values than patients rated low. Also, patients who reattempted or committed suicide during a 5-year follow-up period had significantly higher Km values than controls. Among women patients who had attempted suicide there was a significant correlation between extrapunitive hostility scores and Km values. CONCLUSION: The serotonin transporter warrants further study in relation to suicidal behavior in depression.     

Platelet tritiated imipramine binding and serotonin uptake in depressed patients and controls. Relationship to plasma cortisol levels before and after dexamethasone administration

We measured platelet tritiated imipramine binding and serotonin uptake in 51 depressed patients and 43 normal controls. Although there were no significant differences in platelet 3H-imipramine binding or serotonin uptake when the total group of depressed patients was compared with controls, depressed women (n = 32) had a significantly lower maximal density of 3H-imipramine binding sites (beta max) than control women (n = 25). Moreover, among the total group of depressed patients, there were significant negative correlations between the beta max values and plasma cortisol levels at 4 PM (n = 41) and 11 PM (n = 41) following dexamethasone administration. These negative correlations between beta max and cortisol levels were strongest among melancholic patients both at 4 PM before dexamethasone administration (n = 14) and at 11 PM after dexamethasone administration (n = 15). These data suggest that the reported decrease in beta max found among depressed patients may be related to and is perhaps secondary to the hypercortisolemia of depression.     

Clinical effects of L-5-hydroxytryptophan administration in chronic schizophrenic patients.

L-5-Hydroxytryptophan (L-5HTP) and the peripheral decarboxylase inhibitor carbidopa were administered to chronic schizophrenic patients in three separate experiments using a double-blind placebo-controlled crossover design. The three experiments were: (i) L-5HTP administration to 15 patients who had been withdrawn from all neuroleptic medication; (ii) L-5HTP administration to seven patients maintained on haloperidol; (iii) L-5HTP administration to nine patients maintained on chlorpromazine. Although the groups were diagnostically homogeneous, individual responses were highly variable. Considering each group as a whole, the only significant changes in rated psychosis consisted of an increase in the first group consequent to coming off neuroleptic medication and an increase in psychosis scores associated with adding L-5HTP to chlorpromazine. Neuroleptics apparently sensitize the central nervous system to the effects of L-5HTP loading. Acute exacerbations of psychosis induced by L-5HTP can be reversed by neuroleptics. Our experience does not give encouragement to the hypothesis that schizophrenic illnesses arise consequent to a deficit of serotonergic function that can be treated by giving a serotonin precursor in pharmacological quantities.     

Measurement of 5-hydroxyindole compounds during L-5-HTP treatment in depressed patients.

L-5-hydroxytryptophan (L-5-HTP), an immediate serotonin precursor, was given to the hospitalized depressed patients in an open clinical trial of the Phase 2 study for antidepressive effects of the agent. A relatively small dose, 150mg orally for seven days, was employed, and seven of 14 patients responded to the treatment with mild or moderate emelioration of their depressive symptoms. Urinary excretion levels and plasma concentrations of three 5-hydroxyindole compounds, 5-HTP, 5-HT and 5-HIAA, were measured during the drug treatment. Approximately 70% of the orally administered dose of L-5-HTP was recovered from the urine of depressed patients. Major part of urinary indoleamine metabolites was free and conjugate 5-HIAA. Excretion levels of these compounds in urine were not consistenly altered in the depressed patients as compared to those in normal subjects. Clinical response to L-5-HTP treatment appeared to have some correlation with the biochemical measures in the depressed patients, that is, non-responders exhibited significantly lower excretion levels of 5-HT and 5-HIAA in urine, and lower plasma levels of 5-HT than responders. Administered L-5-HTP may not be fully utilized in the depressed patients who did not react to the agent.     

Platelet reactivity in depressed patients treated with paroxetine: preliminary findings

BACKGROUND: Alterations in platelet reactivity have been previously posited to underlie the increased vulnerability of patients with depression to ischemic heart disease (IHD). The present study sought to determine whether the increased platelet reactivity associated with major depression is reduced after antidepressant treatment. METHODS: Patients diagnosed as having DSM-IV major depression (n = 15) (mean age, 37 +/- 7 years; range, 23-48 years) and 12 normal comparison subjects (mean age, 36 +/- 7; range, 23-48 years) were recruited. None of the controls or depressed group had evidence of IHD; 10 of 15 patients who were depressed had 1 or more traditional IHD risk factors. In vivo platelet activation, secretion, and dose-response aggregation of the controls and patients was measured after overnight bedrest under basal conditions, and after a mild exercise challenge. After 6 weeks of open-label treatment with the selective serotonin reuptake inhibitor paroxetine (20 mg/d), the patients with depression were readmitted and procedures of the first General Clinical Research Center admission repeated. RESULTS: In comparison with the control group, the depressed group exhibited greater procoagulant activity as detected by increased platelet binding of the monoclonal antibodies anti-ligand-induced binding site and GA6, and increased plasma concentrations of platelet factor 4 under basal conditions. After paroxetine treatment, the patients with depression exhibited significant reductions in all 3 parameters. CONCLUSIONS: Normalization of platelet activation is associated with paroxetine treatment of patients with depression. Because this study design did not allow for the determination of whether this effect of paroxetine on platelet function is caused by a direct effect of the drug or placebo or, alternatively, because of recovery from depression, studies containing a placebo and/or psychotherapy treatment arm may resolve this issue.