Which patients with bipolar depression receive antidepressant augmentation? Results from an observational multicenter study.

BACKGROUND: To identify demographic and clinical characteristics of bipolar depressed patients who require antidepressant (AD) augmentation, and to evaluate the short- and long-term effectiveness and safety of this therapeutic strategy. METHODS: One hundred twenty-two bipolar depressed patients were consecutively recruited, 71.7% of them received mood stabilizers (MS)/second-generation antipsychotics (SGA) with AD-augmentation and 28.3% did not. Patients were evaluated at baseline, and after 12 weeks and 15 months of treatment. RESULTS: The AD-augmentation was significantly higher in patients with bipolar II compared with bipolar I diagnosis. Patients with MS/SGA + AD had often a seasonal pattern, depressive polarity onset, depressive index episode with anxious features, a low number of previous psychotic and (hypo)manic episodes and of switch. They had a low irritable premorbid temperament, a low risk of suicide attempts, and a low number of manic symptoms at baseline. After 12 weeks of treatment, 82% of patients receiving ADs improved, 58% responded and 51% remitted, 3.8% had suicidal thoughts or projects, 6.1% had (hypo)manic switch, and 4.1% needed hospitalization. During the following 12 months, 92% of them remitted from index episode, 25.5% did not relapse, and 11% needed hospitalization. Although at the start advantaged, patients with AD-augmentation, compared with those without AD-augmentation, did not significantly differ on any outcome as well on adverse events in the short- and long-term treatment. CONCLUSION: Our findings indicate that ADs, combined with MS and/or SGA, are short and long term effective and safe in a specific subgroup for bipolar depressed patients.

Neurodevelopmental Disorders, Schizophrenia Spectrum Disorders and Catatonia: The "Iron Triangle" Rediscovered in a Case Report.

Catatonia is a complex neuropsychiatric syndrome, occurring in the context of different psychiatric and neurodevelopmental disorders, in neurological and medical disorders, and after substance abuse or withdrawal. The relationship between Autism Spectrum Disorder (ASD), Schizophrenia Spectrum Disorders (SSDs) and catatonia has been previously discussed, with the three disorders interpreted as different manifestations of the same underlying brain disorder (the "Iron Triangle"). We discuss in this paper the diagnostic, clinical and therapeutic implications of this complex relationship in an adolescent with ASD, who presented an acute psychotic onset with catatonia, associated with mixed mood symptoms. Second-generation antipsychotics were used to manage psychotic, behavioral and affective symptoms, with worsening of the catatonic symptoms. In this clinical condition, antipsychotics may be useful at the lowest dosages, with increases only in the acute phases, especially when benzodiazepines are ineffective. Mood stabilizers with higher GABAergic effects (such as Valproate and Gabapentin) and Lithium salts may be more useful and well tolerated, given the frequent association of depressive and manic symptoms with mixed features.

Is short-term antidepressant treatment effective and safe in bipolar depression? Results from an observational multicenter study.

OBJECTIVES: To investigate the short-term effectiveness and the short-term and long-term safety of acute antidepressant (AD) treatment of bipolar depression in a naturalistic setting. METHODS: Patients with bipolar (n = 86) or unipolar (n = 111) depression were consecutively recruited and treated with AD (combined with mood stabilizer [MS] and/or second-generation antipsychotics in bipolar depression). Exclusion criteria were mixed depression, high mood instability, previous predominantly mixed depression (both bipolar and unipolar depression), rapid cycling course and previous switch AD-emerging (bipolar depression). RESULTS: After 12 weeks of treatment, no difference was found in remission, response and improvement rates between bipolar and unipolar depression. Concerning short-term safety, switching and suicidality did not differ significantly between the two groups, and no suicide attempt was observed. Concerning long-term safety, patients with bipolar depression had a significant reduction of depressive and total recurrences during the year of follow-up, compared to the year before entering the study, without significant changes in (hypo)mania and mixed depression recurrences, and suicide rates. CONCLUSIONS: Acute AD treatment of bipolar depression is effective in the short-term and safe in the short- and long-term, when administered in combination with MSs and/or second-generation antipsychotics, with a low risk of switch, mixed depression and cycle acceleration.

The relationship between depression with anxious distress DSM-5 specifier and mixed depression: a network analysis.

INTRODUCTION: Epidemiological, clinical, and treatment response characteristics of major depression with anxious distress (ADS) are quite similar to those of mixed depression, but no study investigated the symptom interplay of these conditions. OBJECTIVE: To analyze the correlations among symptom criteria for major depression with ADS and for mixed depression using a network analysis. METHODS: Two hundred and forty-one outpatients with major depression were consecutively recruited. DSM-5 criteria for major depression with ADS or with mixed features (MF) and Koukopoulos' criteria for mixed depression (MXD) were assessed using a structured clinical interview. RESULTS: A total of 58.9% of patients met DSM-5 criteria for major depression with ADS, 48.5% for MXD, and 2.5% for major depression with MF, so that the symptoms of this specifier were excluded from the network analysis. The most frequent symptoms were difficulty concentrating due to worries (57.7%), feeling keyed up or on edge (51%) (major depression with ADS), and psychic agitation or inner tension (51%) (MXD). Psychic agitation or inner tension had a central position in the network and bridged MXD to major depression with ADS through feeling keyed up or on edge. CONCLUSIONS: Criteria for major depression with ADS and for MXD are partially overlapping, with psychic agitation or inner tension and feeling keyed up or on edge that feature in both conditions and are difficult to distinguish in clinical practice. The clarification of the relationship between these two psychopathological conditions could bring important implications for diagnosis, prognosis, and treatment of depressive episodes.

Fabry cardiomyopathy: Gb3-induced auto-reactive panmyocarditis requiring heart transplantation.

Resistance to enzyme replacement therapy (ERT) is a major therapeutic challenge in Fabry disease (FD). Recent reports attribute to immune-mediated inflammation a main role in promoting disease progression and resistance to ERT. Aim of the study is to report a Gb3-induced auto-reactive panmyocarditis causing inefficacy of ERT and severe electrical instability, which required cardiac transplantation. Examining the explanted heart from a 57-year-old man with FD cardiomyopathy (CM) on 3-year ERT presenting incoming ventricular fibrillation, we documented a severe virus-negative myocarditis extended to cardiomyocytes, intramural coronary vessels, conduction tissue, and subepicardial ganglia. Serology was positive for anti-Gb3, anti-heart, and anti-myosin antibodies. In vitro Gb3 stimulation of patient's peripheral blood mononuclear cells (PBMC) induced high amount production of inflammatory cytokine IL1-ß, IL-6, IL-8, and TNF-α. PBMC were stained using the monoclonal antibodies CD3-V500, CD4-V450, CD8-APCcy7, CD45RO-PerCPcy5.5 and CD27-FITC from BD Biosciences and CD56-PC7 from Bekman Coulter. The phenotypic analysis of PBMC showed a lower frequency of CD8 (9.2%) vs. 19.3% and NKT cells (1.6% vs. 2.4%) in Fabry patient respect to healthy donor, suggesting a possible homing to peripheral tissues. A Gb3-induced auto-reactive myocarditis is suggested as a possible cause of FDCM progression and ERT resistance. Immune-mediated inflammation of systemic Fabry cells may coexist and be controlled by implemental immunosuppressive therapy.

Infarct-like myocarditis with coronary vasculitis and aneurysm formation caused by Epstein-Barr virus infection

Myocardial infection by Epstein-Barr virus (EBV) may manifest with inflammatory cardiomyopathy, coronary syndrome X, and rarely with infarct-like myocarditis. The aim of the report is to describe a case of myocardial EBV infection causing acute myocarditis with heart failure, necrotizing coronary vasculitis, and multiple left ventricular (LV) aneurysms. A 67-year-old woman presented with fever, chest pain, and heart failure. She underwent non-invasive cardiac studies including electrocardiography, 2D-echocardiography, cardiac magnetic resonance, hematochemical exams with Troponin T determination, and invasive studies including cardiac catheterization, coronary angiography, and LV endomyocardial biopsy. Five endomyocardial samples were processed for histology and immunohistochemistry for inflammatory cells characterization and detection of viral antigens. Two additional frozen samples were evaluated by real-time polymerase chain reaction for the presence of cardiotropic viral genomes. Routine laboratory tests revealed the presence of elevated white blood cells (17 000 103 /µL) and increased Troponin T. Electrocardiogram showed sinus tachycardia with ST elevation in V2-V5. Two-dimensional echocardiography showed normal LV dimension with reduced LV contractility (LVEF = 40%) with mild pericardial effusion. Cardiac magnetic resonance revealed the presence of a micro-aneurism in the inferior LV wall, a diffuse oedematous imbibition of LV myocardium suggested by hyper-intensity of T2 mapping, and increased fibrosis as suggested by areas of late gadolinium enhancement signals. Coronary arteries were normal while several micro-aneurysms were observed at LV angiography. At histology, a lymphocytic myocarditis with necrotizing coronary vasculitis sustained by a positive real-time polymerase chain reaction for EBV, detectable in cardiomyocytes and inflamed intramural vessels by positive immunohistochemistry for EBV latent membrane protein 1 antigen, was observed. Myocardial EBV infection is an unusual cause of acute heart failure and cardiac aneurysms, increasing the risk of electrical instability, cardiac perforation, and sudden death.

Toxoplasmosis in a Cohort of Italian Patients With Bipolar and Psychotic Disorders: How Infection May Affect Clinical Features?

This study investigated the seroprevalence of Toxoplasma gondii in a cohort of 101 Italian inpatients affected by mood or schizophrenia-spectrum disorders and compared clinical features between seronegative and seropositive subjects. Patients diagnosed according to DSM-5 criteria underwent clinical assessments and blood collection to test parasite-specific IgG/IgM serum levels. Twenty-eight patients (27.7%) had IgG anti-T. gondii, and none had IgM antibodies. We found higher prevalence rate in patients aged 40 years or older, as compared with younger. No significant association was detected between T. gondii and a specific diagnostic category; however, bipolar disorder (BD)-II showed the highest positivity rate (40.9%). The seropositive status was significantly associated with a lower presence of psychotic symptoms, higher number of total episodes of predominant excitatory polarity, longer illness duration, and lower severity of current episode, particularly anxiety, depressive, and withdrawal/retardation symptoms. These preliminary results seem to point out an association between chronic toxoplasmosis and a specific subtype of BD.

Non-Functional Trace Amine-Associated Receptor 1 Variants in Patients With Mental Disorders.

Background: The G protein-coupled receptor (GPCR) trace amine-associated receptor 1 (TAAR1) is expressed across brain areas involved in emotions, reward and cognition, and modulates monoaminergic and glutamatergic neurotransmissions. TAAR1 is stimulated with nanomolar affinity by 3-iodothyronamine (T1AM), an endogenous messenger considered a novel branch of thyroid hormone signaling. The human gene for TAAR1 maps to locus 6q23, within a region associated with major mental disorders. Materials and Methods: We screened a cohort of patients with major mental disorders (n = 104) and a group of healthy controls (n = 130) for TAAR1 variants. HEK293 cells were transiently transfected with: i) wild-type TAAR1 and ii) mutated TAAR1, either in homozygous or heterozygous state. Cell surface expression and Gs/adenylyl cyclase activation upon administration of ß-phenylethylamine (PEA), T1AM, and RO5166017, were assessed. Results: We detected 13 missense variants in TAAR1 coding region, with a significant enrichment in patients as compared to healthy controls (11 vs. 1, 1 variant in both groups, p < 0.01). In silico analysis identified four dysfunctional variants, all in patients. Three of these-R23C, Y131C, and C263R-were functionally characterized. In cells co-transfected with wild-type and mutated TAAR1, we observed a significant reduction of cell surface expression. In heterozygosity, the three TAAR1 variants substantially dampened Gs signaling in response to PEA, and, more robustly, to T1AM. Co-stimulation with PEA and RO5166017 did not yield any improvement in Gs signaling. R23C, Y131C, and C263R are rare in the general population and map in functionally important highly conserved positions across TAAR1 orthologous and paralogous genes. Conclusions: Our findings suggest that disruptions of TAAR1 activity may be relevant to the pathophysiology of mental disorders, thereby providing a promising target for novel psychopharmacological interventions.

Primary aldosteronism-associated cardiomyopathy: Clinical-pathologic impact of aldosterone normalization.

BACKGROUND: Primary aldosteronism (PA) causes a cardiomyopathy (CM) which substrate and evolution after aldosterone normalization are unreported. METHODS: Four male patients with aldosterone-secreting adrenal adenoma and cardiomyopathy (PACM, group A) were evaluated with 2D-echo, Magnetic Resonance (CMR), coronary angiography and left ventricular endomyocardial biopsy. Biopsy samples were processed for histology, electron microscopy, immunohistochemistry, and Western Blot analysis of myocardial aldosterone receptors and aquaporin 1 and 4. Results were compared with endomyocardial samples from 5 patients with hypertensive cardiomyopathy of equivalent severity and normal plasma aldosterone (group B) and surgical samples from 5 controls (group C). One PACM patient was re-examined with CMR and endomyocardial biopsy 12 months after adrenalectomy with aldosterone and cardiac normalization. RESULTS: Coronary arteries were normal in all. Group A showed prominent myocardial hypertrophy and fibrosis, with water accumulation in the cytosol and organelles of cardiomyocytes and microvascular smooth muscle cells, associated to reduced myofibril concentration and 2.8-fold increase in myocardial aldosterone receptors and aquaporin 1. At CMR, LGE areas were diffusely present. After aldosterone normalization, cardiomyocyte diameter reduced with disappearance of intracellular vacuoles, recovery of electron-density of cytosol and cell organelles, and myofibrillar content, persisting fibrosis and down-regulation of aldosterone receptors and aquaporin 1 channels. At CMR, myocardial mass reduced with recovery of cardiac contractility. LGE signal remained unchanged. CONCLUSION: PACM is a reversible entity characterized by over-expression of aldosterone receptors and aquaporin 1. It induces a reversible intracellular water overloading causing impaired cardiomyocyte relaxation, contraction and ultrastructural integrity.

Lithium and valproate serum level fluctuations within the menstrual cycle: a systematic review.

Some women affected by mood disorders experience mood instability during the premenstrual phase. Assuming that fluctuations in drug serum levels may contribute to the worsening of mood symptoms, we carried out a systematic review of available studies that investigated changes in lithium and valproate levels in relation to menstrual phases. We selected five studies; four of which assessed menstrual fluctuations in lithium serum levels and one in valproate levels. Study samples included women in their fertile age affected by bipolar disorder, epilepsy as well as healthy ones. Preliminary results showed a close relationship between cyclic premenstrual exacerbation of affective symptoms and a significant decrease in lithium levels during the luteal phase, despite stable oral doses, in bipolar women. In healthy women, lithium levels were influenced by neither menstrual cycle phases nor oral contraceptives use. Valproate serum levels in epileptic women showed a small, nonsignificant decline during the mid-luteal phase. Pharmacokinetic sex differences in adsorption, volume distribution, hepatic metabolism, and renal excretion of mood stabilizers have been supposed to partly explain such menstrual serum level fluctuations. A better understanding in this field could help to counteract the distress related to premenstrual phase, improving therapeutic management of mood disorders in women.

Is there a relationship between depression with anxious distress DSM-5 specifier and bipolarity? A multicenter cohort study on patients with unipolar, bipolar I and II disorders.

BACKGROUND: To estimate the prevalence of DSM-5 anxious distress specifier (ADS) in depressed patients with major depressive disorder (MDD) or bipolar I or II disorder (BD), and to compare socio-demographic and clinical characteristics, and response to naturalistic short-term treatment between ADS and non-ADS group. METHODS: 241 outpatients with a major depressive episode (MDE) were consecutively recruited. Outcome were remission (HDRS21 total score < 7), response (≥50% reduction of baseline HDRS21) and improvement (CGI-i score ≤ 2) after 12 weeks of treatment sustained for 4 weeks. RESULTS: ADS was more frequent in BD than in MDD (respectively, 66.9% and 51.2%, χ2 = 6.1, p = 0.013). Compared with those non-ADS, patients with ADS had more severe depressive (respectively, HDRS21 total score 20.0 ±â€¯4.4 and 18.6 ±â€¯3.9, t-test = 2.67, p = 0.008) and mania symptoms (respectively, Y-MRS total score 2.2 ±â€¯2.9 and 1.3 ±â€¯2.3, M-W-test = 2.86; p = 0.004) at intake, a higher rate of BD family history (respectively, 35.2% and 22.2%, Χ2-test 10.4, p = 0.004) and more previous hypomanic episodes (respectively, (median (range) 0 (0-20) and 0 (0-15), MW-test = 2.39 p = 0.017). In the MDD group, patients with ADS had higher scores on hyperthymic temperament and mania symptoms (Y-MRS total score (median (range) 2.2 (0-26) and 0 (0-11), respectively, M-W test 2.071, p = 0.038). ADS and no-ADS patients did not significantly differ on outcome measures. LIMITATIONS: The observational nature of the study and the absence of blinding in outcome assessment. CONCLUSIONS: ADS is the most common DSM-5 specifier for MDE, is more frequent in BD and need a personalized treatment with moderate use of antidepressants, mostly tricyclic.

Lithium, valproate, and carbamazepine prescribing patterns for long-term treatment of bipolar I and II disorders: A prospective study.

OBJECTIVE: This study aims to describe the prescription patterns of the mood stabilizers most commonly used for the treatment of bipolar I and II disorders (lithium, valproate, and carbamazepine) and to analyze the treatment outcomes. METHODS: Two hundred and thirty-four outpatients with bipolar disorders receiving prophylactic treatment with lithium, valproate, carbamazepine, or their combination were followed up for at least 18 months in two Italian psychiatric centers specialized in mood disorders. RESULTS: The combination of lithium and valproate or carbamazepine was the most common prophylactic treatment (54.3%), followed by valproate or carbamazepine (24%) and lithium monotherapy (22%). Polytherapy was prescribed mainly to patients with bipolar I disorder, a high number of previous episodes and lifetime psychotic symptoms, whereas valproate or carbamazepine monotherapy was prescribed to patients with anxiety comorbidity. The annual frequency of recurrences decreased significantly after entering the study in the overall sample, and the reduction was significantly higher in patients on lithium plus valproate or carbamazepine compared with the valproate or carbamazepine group, but not with the lithium monotherapy group. The number of mixed recurrences during the follow-up was significantly higher in patients on lithium plus valproate or carbamazepine. CONCLUSIONS: Our findings may help clinicians to personalize long-term treatment to prevent relapses of bipolar disorder according to clinical presentation.

Immune-Mediated Myocarditis in Fabry Disease Cardiomyopathy.

Background Glycosphingolipid accumulation in Fabry cells generates a proinflammatory response that may influence disease evolution and responsiveness to enzyme replacement therapy. This study evaluated incidence, mechanism, and impact of myocarditis in Fabry disease cardiomyopathy ( FDCM ). Methods and Results Myocarditis, defined as CD 3+ T lymphocytes >7/mm2 associated with necrosis of glycolipid-laden myocardiocytes, was retrospectively evaluated in endomyocardial biopsies from 78 patients with FDCM : 13 with maximal wall thickness (MWT) <11 mm (group 1), 17 with MWT 11 to 15 mm (group 2), 30 with MWT 16 to 20 mm (group 3), and 18 with MWT >20 mm (group 4). Myocarditis was investigated by polymerase chain reaction for cardiotropic viruses, by serum antiheart and antimyosin antibodies, and by cardiac magnetic resonance. Myocarditis was recognized at histology in 48 of 78 patients with FDCM (38% of group 1, 41% of group 2, 66% of group 3, and 72% of group 4). Myocarditis was characterized by positive antiheart and antimyosin antibodies and negative polymerase chain reaction for viral genomes. CD 3+ cells/mm2 correlated with myocyte necrosis, antimyosin autoantibody titer, and MWT ( P<0.001, r=0.79; P<0.001, r=0.84; P<0.001, r=0.61, respectively). Cardiac magnetic resonance showed myocardial edema in 24 of 78 patients (31%): 0% of group 1, 23% of group 2, 37% of group 3, and 50% of group 4. Conclusions Myocarditis is detectable at histology in up to 56% of patients with FDCM . It is immune mediated and correlates with disease severity. It can be disclosed by antiheart/antimyosin autoantibodies and in the advanced phase by cardiac magnetic resonance. It may contribute to progression of FDCM and resistance to enzyme replacement therapy.

Neuroimaging Profiles and Neurodevelopmental Outcome in Infants With Congenital Cytomegalovirus Infection.

BACKGROUND: The accurate stratification of infants with congenital cytomegalovirus (CMV) infection at risk for more severe outcome may help in the management of patients. Aim of this study was to investigate the ability of a comprehensive neuroimaging investigation in predicting the long-term neurodevelopmental outcome in patients with congenital CMV. We analyzed the prognostic accuracy of a traditional score and a recently proposed scale applied to head ultrasound (HUS), computed tomography (CT) and magnetic resonance imaging (MRI). METHODS: All consecutive neonates born from 2002 to 2015 with congenital CMV infection were considered eligible for the study. Neuroimaging findings were scored according to both scores. RESULTS: One hundred seventy infants were included (112 symptomatic patients). One-hundred eighteen infants received both HUS, CT and MRI. CT and MRI were normal in all 56 asymptomatic patients, while 32% of them presented an abnormal HUS. The prevalence of abnormal findings differed according to the neuroimaging study. The sensitivity of the new neuroimaging score in detecting patients at risk for poor neurologic outcome was higher than the traditional one for all neuroimaging examinations. CT and MRI showed higher positive predictive value compared with HUS. No neuroimaging examination showed a negative predictive value equal to 100%. CONCLUSIONS: Although HUS is the safest neuroimaging technique, it performs less well in detecting some brain abnormalities that can be associated with a poor neurodevelopmental outcome. A comprehensive neuroimaging evaluation is mandatory in infants with congenital CMV infection to decide for treatment and make a prognostic evaluation.

Myocardial expression of Toll-like receptor 4 predicts the response to immunosuppressive therapy in patients with virus-negative chronic inflammatory cardiomyopathy.

AIMS: We sought to determine whether myocardial expression of Toll-like receptor 4 (TLR4) may predict the response to immunosuppression. METHODS AND RESULTS: Endomyocardial biopsies from 237 patients with virus-negative inflammatory cardiomyopathy treated with immunosuppression were retrospectively examined for the expression of TLR4, differentiating those patients responding to immunosuppression (n = 193) from non-responder patients (n = 44). A semiquantitative evaluation of the immunoreactivity (grading from 0 to 4) for TLR4 and human leucocyte antigen (HLA)-DR was performed together with real-time PCR and western blot for TLR4. Cardiomyocyte apoptosis and necrosis was evaluated by in situ ligation with hairpin probes. A focal intense positive cytoplasmic immunostaining for TLR4 was observed in cardiomyocytes of all responders (P < 0.001 vs. non-responders). A grading 2 or above (2+) at baseline showed a sensitivity of 100% and 90.9% specificity with a positive predictive value of 98% as a predictor of an immunosuppression-positive response. Real-time PCR and western blot analysis for TLR4 were 4.3-fold and 4.6-fold higher, respectively, in responders vs. non-responders. Correlation between TLR4 grading and TLR4 mRNA molecular and protein expression was highly significant. HLA-DR did not discriminate between the two groups. Cardiomyocyte death by apoptosis was 3.7-fold higher in responders vs. non-responders and significantly correlated with TLR4 expression, while necrosis was comparable. Intensity of baseline TLR4 expression correlated with the variation in ejection fraction after 6 months of immunosuppression. CONCLUSION: TLR4 is highly expressed in human myocarditis responding to immunosuppression. It can be considered as a new sensitive marker in patient selection predicting a good response to immunosuppressive therapy.

Is Toxoplasma gondii a Trigger of Bipolar Disorder?

Toxoplasma gondii, a ubiquitous intracellular parasite, has a strong tropism for the brain tissue, where it forms intracellular cysts within the neurons and glial cells, establishing a chronic infection. Although latent toxoplasmosis is generally assumed to be asymptomatic in immunocompetent individuals, it is now clear that it can induce behavioral manipulations in mice and infected humans. Moreover, a strong relation has emerged in recent years between toxoplasmosis and psychiatric disorders. The link between T. gondii and schizophrenia has been the most widely documented; however, a significant association with bipolar disorder (BD) and suicidal/aggressive behaviors has also been detected. T. gondii may play a role in the etiopathogenesis of psychiatric disorders affecting neurotransmitters, especially dopamine, that are implicated in the emergence of psychosis and behavioral Toxoplasma-induced abnormalities, and inducing brain inflammation by the direct stimulation of inflammatory cytokines in the central nervous system. Besides this, there is increasing evidence for a prominent role of immune dysregulation in psychosis and BD. The aim of this review is to describe recent evidence suggesting a link between Toxoplasma gondii and BD, focusing on the interaction between immune responses and this infectious agent in the etiopathogenesis of psychiatric symptoms.