Quetiapine Abuse Fourteen Years Later: Where Are We Now? A Systematic Review.

Background: Quetiapine, an atypical antipsychotic endowed with weak dopamine antagonist, potent 5-HT2A-blocking, partial 5-HT1A-agonist, anti-H1 histamine, adrenolytic, and sigma1 receptor agonist activities, since an original 2004 report is increasingly misused. Although some of its pharmacodynamics might explain some motives for voluptuary use, most of its actions are directed at setting-off those motives. Hence, it is possible that its popularity in special populations is due to the fact that the unpleasant or unwanted effects of addiction substances are somehow soothed by quetiapine. Currently, quetiapine is tested in substance use disorders, showing some promise, but it is likely to be misused in certain contexts. Objectives: To review the evidence for the use of quetiapine as addiction substance and investigate the characteristics of populations involved in such addiction. Methods: A systematic review of literature on various databases retrieved on September 7, 2018 87 records to comment. Results. We reviewed the evidence for quetiapine's addictive potential in the light of its pharmacodynamics properties and presented two cases of recreational quetiapine use, by a 35-year old male patient with past addictive behavior and by a 50-year-old woman with major depressive disorder and conversion disorder. We found quetiapine to be abused mainly by addict populations and people with law involvement. Conclusions/Importance: There is no reason to include quetiapine among regulated substances, but monitoring of its use in selected populations is warranted. Psychiatrists and physicians working in the penitentiary system should be aware of the addictive potential of quetiapine and adopt measures restricting its use.

Placebo Effect in Obsessive-Compulsive Disorder (OCD). Placebo Response and Placebo Responders in OCD: The Trend Over Time.

BACKGROUND: Placebo response appears to be increasing in antidepressant, antipsychotic and various internal medicine trials. A similar trend has been reported for OCD during 1989-1999. Placebo response is generally considered as the extent to which placebo treatment is associated with core symptom improvement. In this analysis, we used Joinpoint regression to assess the time trend of both placebo response and placebo responder rates according to the year of publication with no time restriction in OCD drug trials. METHODS: We included drug and/or psychotherapy trials vs. placebo from PubMed, Embase, CINAHL, and PsycINFO retrieved through the search (placebo OR sham) AND (obsessive* OR OCD). We included studies through investigator consensus. We then performed on data of included studies log-linear joinpoint segmented regression models using a p<0.05 cutoff. RESULTS: We included 113 studies from 112 published papers. Placebo mean annual response rates in OCD studies significantly increased from 1991 to 2017 with an annual percent change (APC) of 0.66%, while placebo mean annual responder rates also significantly increased from 2010 to 2017, with an APC of 5.45%. Drug mean annual response rates in OCD studies significantly increased from 1987 to 2012 with an APC of 0.72%, while the corresponding responder rates did not show statistically significant APC changes between 1984 and 2017. CONCLUSION: We observed a tendency for placebo to increase both measures of response in OCD clinical drug trials through the years that tend to approximate the responses shown by drugs. Changes in the type of study (moving from classical head to head comparisons to add-on studies in treatmentresistant populations) and countries involved in experimentation may partially account for some portion of these results. It appears that placebo effects are becoming more elusive and out of control.

Neurobiological Evidence for the Primacy of Mania Hypothesis.

BACKGROUND: Athanasios Koukopoulos proposed the primacy of mania hypothesis (PoM) in a 2006 book chapter and later, in two peer-reviewed papers with Nassir Ghaemi and other collaborators. This hypothesis supports that in bipolar disorder, mania leads to depression, while depression does not lead to mania. OBJECTIVE: To identify evidence in literature that supports or falsifies this hypothesis. METHOD: We searched the medical literature (PubMed, Embase, PsycINFO, and the Cochrane Library) for peer-reviewed papers on the primacy of mania, the default mode function of the brain in normal people and in bipolar disorder patients, and on illusion superiority until 6 June, 2016. Papers resulting from searches were considered for appropriateness to our objective. We adopted the PRISMA method for our review. The search for consistency with PoM was filtered through the neurobiological results of superiority illusion studies. RESULTS: Out of a grand total of 139 records, 59 were included in our analysis. Of these, 36 were of uncertain value as to the primacy of mania hypothesis, 22 favoured it, and 1 was contrary, but the latter pooled patients in their manic and depressive phases, so to invalidate possible conclusions about its consistency with regard to PoM. All considered studies were not focused on PoM or superiority illusion, hence most of their results were, as expected, unrelated to the circuitry involved in superiority illusion. A considerable amount of evidence is consistent with the hypothesis, although indirectly so. LIMITATIONS: Only few studies compared manic with depressive phases, with the majority including patients in euthymia. CONCLUSION: It is possible that humans have a natural tendency for elation/optimism and positive self-consideration, that are more akin to mania; the depressive state could be a consequence of frustrated or unsustainable mania. This would be consistent with PoM.

The Italian version of the 92-item Prodromal Questionnaire: Concurrent validity with the SIPS and factor analysis in a sample of 258 outpatients aged 11-36years.

BACKGROUND: Current early screeners for psychosis-risk states have still to prove ability in identifying at-risk individuals. Among screeners, the 92-item Prodromal Questionnaire (PQ-92) is often used. We aimed to assess the validity of its Italian translation in a large Italian adolescent and young adult help-seeking sample. METHODS: We included all individuals aged 12-36years seeking help at psychiatric mental health services in a large semirural Roman area (534,600 population) who accepted to participate. Participants completed the Italian version of the PQ-92 and were subsequently assessed with the Structured Interview of Prodromal/Psychosis-Risk Syndromes (SIPS). We examined diagnostic accuracy (sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios) and content, concurrent, and convergent validity between PQ-92 and SIPS using Cronbach's alpha, Cohen's kappa, and Spearman's rho, respectively. We tested the validity of adopted cut-offs through Receiver Operating Characteristic (ROC) curves plotted against SIPS diagnoses and the instrument's factor-structure through Principal Component Analysis. RESULTS: PQ-92 showed high internal consistency, acceptable diagnostic accuracy and concurrent validity, and excellent convergent validity. ROC analyses pointed to scores of 18 on the Positive subscale and 36 on the total PQ-92 as best cut-offs. The Scree-test identified a four-factor solution as fitting best. CONCLUSIONS: Psychometric properties of Italian PQ-92 were satisfactory. Optimal cut-offs were confirmed at ≥18 on the positive subscale, but at ≥36 on the total scale was able to identify more SIPS-positive cases.

Pain perception and hypnosis: findings from recent functional neuroimaging studies.

Hypnosis modulates pain perception and tolerance by affecting cortical and subcortical activity in brain regions involved in these processes. By reviewing functional neuroimaging studies focusing on pain perception under hypnosis, the authors aimed to identify brain activation-deactivation patterns occurring in hypnosis-modulated pain conditions. Different changes in brain functionality occurred throughout all components of the pain network and other brain areas. The anterior cingulate cortex appears to be central in modulating pain circuitry activity under hypnosis. Most studies also showed that the neural functions of the prefrontal, insular, and somatosensory cortices are consistently modified during hypnosis-modulated pain conditions. Functional neuroimaging studies support the clinical use of hypnosis in the management of pain conditions.

[Basic symptoms and neurocognition: preliminary comparison of first-episode psychosis vs multi-episode long-term illness]. / Sintomi base e neurocognizione: confronto preliminare dell'esordio psicotico vs malattia di lunga durata.

BACKGROUND: Schizophrenia is preceded by basic symptoms which may persist after long time and include subjective cognitive impairment. Furthermore, it is characterised by cognitive deficits that may deteriorate with the progression of illness. To examine the relationship between neurocognition and basic symptoms along the course of schizophrenia, we compared the cognitive performance and the basic symptoms of one population with first episode psychosis (FEP) and one with a chronic, multi-episode course (MEP). METHODS: We tested 8 FEP (5 male) and 7 MEP (7 male) in- and outpatients, for basic symptoms with the Schizophrenia Proneness Instrument-Adult version (SPI-A) and for neurocognition with Raven's Color Progressive Matrices (CPM), Rey-Osterrieth's complex figure (Rey), Corsi's and Buschke-Fuld tests, the Wisconsin Card Sorting Test (WCST), the Stroop test, and the Trail Making Test (TMT). RESULTS: FEP patients did not differ from MEP patients as for SPI-A scores. MEP patients were significantly more impaired on several subtests of Buschke-Fuld, the Rey, and the WCST with respect to FEP. Impairment on the cognitive subscale of the SPI-A correlated with non-perseverative WCST errors, and on the self subscale of the SPI-A with impaired performance on the Buschke-Fuld. Further, in MEP, impairment on the body subscale of the SPI-A correlated inversely with number of categories completed of the WCST. CONCLUSIONS: Basic symptoms persist throughout the phases of schizophrenia and are relatively independent of cognitive performance. A chronic, multi-episode course is associated with increased cognitive impairment in schizophrenia.

Epilepsy and brain injury: a case report of a dramatic neuropsychiatric vicious circle.

PRIMARY OBJECTIVE: Early treatment of epilepsy is warranted to avoid possible severe consequences. This study aimed to assess the value of treatment in a patient who developed epilepsy after major brain surgery. DESIGN: Case description. A 51 years-old man had a history of putative petit mal seizures since adolescence and left frontotemporal lobectomy after a major traffic accident at age 17. He subsequently developed quickly generalizing partial complex seizures, associated with severe behavioural alterations and personality changes; the condition was left untreated. A further seizure-related loss of consciousness led to another traffic accident at age 47. METHODS AND PROCEDURES: The patient was administered 200 mg/day topiramate, 600 mg/day quetiapine, 1000 mg/day valproate, 1200 mg/day gabapentin and 800 mg/day carbamazepine. MAIN OUTCOMES AND RESULTS: The instituted anti-epileptic treatment reduced seizure frequency and severity, but did not affect psychiatric symptomatology, which even worsened. An association between anti-epileptic drugs with mood stabilizing properties and an atypical anti-psychotic dramatically improved psychiatric symptoms, but did not prevent the patient from needing long-term healthcare. CONCLUSIONS: Long-term untreated epilepsy may expose to accident proneness and further psychiatric deterioration. Early diagnosis and treatment of epilepsy may help in avoiding a potentially lethal vicious circle.

Short-term psychodynamic psychotherapy in patients with "male depression" syndrome, hopelessness, and suicide risk: a pilot study.

Objectives and Methods. This was an observational study of the efficacy of short-term psychodynamic psychotherapy (STPP) in a sample of 35 (30 women and 5 men) patients with moderate-to-severe "male depression" (Gotland Scale for Male Depression (GSMD) ≥ 13) comorbid with unipolar mood disorder (dysthymia and major depression) or anxiety disorder. Outcome measures were GSMD and BHS (Beck Hopelessness Scale) score changes from baseline. Results. Patients had a strong response to STPP on the GSMD (estimated mean score change (± SE) = -9.08 ± 2.74; P < 0.01; partial eta squared = 0.50), but not on the BHS (estimated mean score change (± SE) = -0.92 ± 1.55; P = 0.57; partial eta squared = 0.03). BHS score changes were significantly associated with GSMD score changes (Pearson's r = 0.56; P < 0.001), even when controlling for the severity of hopelessness at the baseline (partial r = 0.62; P < 0.001). Conclusions. STPP proved to be effective in patients suffering from "male depression" although hopelessness was only marginally reduced by this treatment which points to the need to better understand how STPP can be involved in the reduction of suicide risk.

Relationships between psychopathological variables and insight in psychosis risk syndrome and first-episode and multiepisode schizophrenia.

Insight may vary across psychosis risk syndrome (PRS), first-episode schizophrenia (FES), or multiepisode schizophrenia (MES). We aimed to compare insight domains (awareness, relabeling, and compliance) in PRS, FES, and MES groups and to correlate scores with psychopathological measures. Insight was assessed in 48 (14 PRS, 16 FES, and 18 MES) patients using the Schedule for the Assessment of Insight-Expanded Version. We conducted psychopathological assessment through the Brief Psychiatric Rating Scale (BPRS). In the whole group, the BPRS psychosis factor correlated with all insight domains. In the MES group, the more severe the anxiety/depression, the higher the insight score in the symptom relabeling domain. Insight did not differ significantly between the PRS, FES, and MES groups. Our results suggest that, across different phases of the illness, lack of insight behaves like a trait and is modulated by positive symptom severity. Anxiety and depression may be associated with increased insight in patients with chronic schizophrenia.

Effectiveness of short-term olanzapine in patients with bipolar I disorder, with or without comorbidity with substance use disorder.

OBJECTIVES: Prognosis of comorbid bipolar disorder (BD) and drug abuse is poor. We assessed the efficacy of olanzapine in manic or mixed BD patients, with (SUD) or without (N-SUD) comorbidity with substance use disorder (SUD) and its effect on drug abuse, days of abuse, and craving. METHODS: Eighty patients with BD-I (40 SUD) were hospitalized for a manic or mixed episode and received add-on olanzapine. Assessments were conducted at admission, discharge, and 4 and 8 weeks after discharge. Primary outcome was the proportion of responders and remitters in each group. We used a logistic regression model to adjust for possible confounders. We assessed craving and drug-abuse days with a visual analog scale and the Timeline Follow-Back. RESULTS: SUD and N-SUD were similar on response and remission, adjusted for sex, age, years ill, age at first episode, first episode depressive, number of hospitalizations, and duration of hospitalization (odds ratio, 1.09; 95% confidence interval, 1.02-2.29). Mood rating scores dropped significantly from baseline to end point in both groups. Timeline follow-back decreased in SUD from 22.5 to 7.3 at 8 weeks postdischarge, whereas craving dropped from 8.3 to 5.1 (P < 0.03). CONCLUSIONS: The effectiveness of short-term olanzapine in BD-I mania or mixed mania did not differ according to SUD comorbidity. Treatment was followed by less substance use/abuse and craving in comorbid bipolar-SUD patients.

Mental disorders diagnosed in childhood and at-risk mental state in a help-seeking population.

AIM: Disorders usually first diagnosed in infancy, childhood or adolescence (DUFD-ICA) may have preceded the onset of psychosis by several years and share some co-morbidity with psychotic disorders, but only a few studies have investigated this aspect. We looked for past or current DUFD-ICA in a sample of first adult psychiatric service users assessed for the presence of an at-risk mental state with the Structured Interview for Psychosis-risk Syndromes (SIPS). METHODS: We interviewed with the SIPS 159 first-time help seekers (age range 13-30 years) at adult psychiatric services who volunteered to participate in the study. For psychiatric diagnoses, we used the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition-Text Revision. We also assessed retrospectively the presence of DUFD-ICA and administered the Brief Psychiatric Rating Scale (BPRS) and the Global Assessment of Functioning. The sample has been subdivided diagnostically into first-episode psychosis, multiple episode psychosis, ultra-high risk (UHR) and other diagnoses. RESULTS: The risk for having one of first-episode psychosis, multiple episode psychosis or UHR was over 3.45 higher in the DUFD-ICA-positive history group than in the non-DUFD-ICA. Grouping the UHR with the not full-blown psychosis cases resulted in a further increase of the risk to 4.71. DUFD-ICA-positive participants scored higher than non-DUFD-ICA on the Positive, Negative and Disorganization scales of the SIPS and on several core-psychotic BPRS items. CONCLUSIONS: A positive history of DUFD-ICA increases the risk of a diagnosis of prodromal or current psychosis at help seeking. Impaired neurodevelopment may be shared among the psychoses and DUFD-ICA.

Neurodevelopment in schizophrenia: the role of the wnt pathways.

OBJECTIVES: To review the role of Wnt pathways in the neurodevelopment of schizophrenia. METHODS: SYSTEMATIC PUBMED SEARCH, USING AS KEYWORDS ALL THE TERMS RELATED TO THE WNT PATHWAYS AND CROSSING THEM WITH EACH OF THE FOLLOWING AREAS: normal neurodevelopment and physiology, neurodevelopmental theory of schizophrenia, schizophrenia, and antipsychotic drug action. RESULTS: Neurodevelopmental, behavioural, genetic, and psychopharmacological data point to the possible involvement of Wnt systems, especially the canonical pathway, in the pathophysiology of schizophrenia and in the mechanism of antipsychotic drug action. The molecules most consistently found to be associated with abnormalities or in antipsychotic drug action are Akt1, glycogen synthase kinase3beta, and beta-catenin. However, the extent to which they contribute to the pathophysiology of schizophrenia or to antipsychotic action remains to be established. CONCLUSIONS: The study of the involvement of Wnt pathway abnormalities in schizophrenia may help in understanding this multifaceted clinical entity; the development of Wnt-related pharmacological targets must await the collection of more data.

Relationship between handedness and persistent emotional distress in adults experiencing an earthquake.

AIM: Post-traumatic emotional distress follows exposure to trauma and may be affected by atypical cerebral lateralisation. We aimed to explore the relationship between handedness and emotional dysfunction in people exposed to a nat-ural disaster. METHODS: About 22 months after an earthquake, 326 exposed adults completed the Edinburgh Handedness Inventory, the Impact of Events Scale-Revised, and the Insomnia Severity Index. RESULTS: Mixed-handed people, compared to right-handed, had a 3.3 fold increase in odds to have emotional distress. Consistent left-handers scored higher than consistent right- and mixed-handers on the ISI scale. CONCLUSIONS: Findings support that lateral preference is associated with emotion-al distress in people exposed to trauma.

Functional neuroimaging in specific phobia.

Specific phobias (SPs) are common, with lifetime prevalence estimates of 10%. Our current understanding of their pathophysiology owes much to neuroimaging studies, which enabled us to construct increasingly efficient models of the underlying neurocircuitry. We provide an updated, comprehensive review and analyze the relevant literature of functional neuroimaging studies in specific phobias. Findings are presented according to the functional neuroanatomy of patients with SPs. We performed a careful search of the major medical and psychological databases by crossing SP with each neuroimaging technique. Functional neuroimaging, mostly using symptom provocation paradigms, showed abnormal activations in brain areas involved in emotional perception and early amplification, mainly the amygdala, anterior cingulate cortex, thalamus, and insula. The insula, thalamus and other limbic/paralimbic structures are particularly involved in SPs with prominent autonomic arousal. Emotional modulation is also impaired after exposure to phobic stimuli, with abnormal activations reported for the prefrontal, orbitofrontal and visual cortices. Other cortices and the cerebellum also appear to be involved in the pathophysiology of this disorder. Functional neuroimaging identified neural substrates that differentiate SPs from other anxiety disorders and separate SP subtypes from one another; the results support current Diagnostic and Statistical Manual of Mental Disorders, 4th edition-Text Revision (DSM-IV-TR) diagnostic subtyping of SPs. Functional neuroimaging shows promise as a means of identifying treatment-response predictors. Improvement in these techniques may help in clarifying the neurocircuitry underlying SP, for both research and clinical-therapeutic purposes.

Neurocognition under hypnosis: findings from recent functional neuroimaging studies.

Functional neuroimaging studies show that hypnosis affects attention by modulating anterior cingulate cortex activation and uncoupling conflict monitoring and cognitive control function. Considering functional changes in the activation of the occipital and temporal cortices, precuneus, and other extrastriate visual areas, which account for hypnosis-induced altered reality perception, the role of mental imagery areas appears to be central under hypnosis. This is further stressed by the fact that motor commands are processed differently in the normal conscious state, deviating toward the precuneus and extrastriate visual areas. Functional neuroimaging also shows that posthypnotic suggestions alter cognitive processes. Further research should investigate the effects of hypnosis on other executive functions and personality measures.

Factitious disorder comorbid with bipolar I disorder. A case report.

We describe a case of factitious disorder with physical and psychological symptoms comorbid with bipolar I disorder in a 37-year-old woman. Since the onset of bipolar disorder, which occurred at the age of 31, she increasingly complained of physical symptoms, compulsively seeking medical and surgical interventions. She has been hospitalised several times and her Munchausen-type factitious disorder recently appeared to be developing into Munchausen by proxy, involving her 11-year-old daughter. The patient adhered poorly to stabilising and antipsychotic drug treatment and did not improve through the years. We here analyse her mood phases, which were always associated with changes in the quality of factitious symptoms, according to whether the disorder was in its depressive phase (somatic complaints and suicidal ideation prevail), or in its manic or mixed phase (medical intervention-seeking and manipulation of clinicians to obtain surgical interventions). We also briefly discuss some important forensic issues to consider in similar cases, mainly stemming from the psychotic aspects of these two co-occurring disorders. Clinicians should be aware of some patients' ability to produce signs and symptoms of physical and/or psychological illness and consult psychiatrists before giving consent to invasive diagnostic procedures or surgery.

Psychosis risk syndrome comorbid with panic attack disorder in a cannabis-abusing patient affected by Arnold-Chiari malformation type I.

OBJECTIVE: An 18-year-old man with Arnold-Chiari malformation (ACM) type I developed sudden panic attacks. He also manifested sleep disorder, cannabis abuse, and psychosis-risk syndrome (PRS). Although with average-superior intelligence, he had executive dysfunction. This prompted us to explore the relation between ACM, cannabis abuse, PRS and panic disorder. METHOD: We report the case and briefly review the literature focusing on ACM and psychiatric disorders. RESULTS: Behavior therapy led to gradual abstinence from cannabis with disappearance of anxiety symptoms. The patient is currently well and maintained on omega-3 polyunsaturated fatty acids. CONCLUSIONS: Locus coeruleus compression and cannabis abuse may have triggered the symptoms, and the latter might also be PRS-related. PRS and anxiety symptoms should be explored in ACM patients to allow better prevention of psychosis and anxiety disorders.

The wnt pathway in mood disorders.

OBJECTIVES: To review the evidence of the involvement of the Wnt signalling pathway in mood disorders and in the action of drugs used to treat these disorders. METHODS: We performed a careful PubMed search using as keywords all possible terms relevant to the Wnt pathway and crossing them with each of four areas, i.e., developmental effects, behavioural effects, mood disorders, and drugs used in their treatment. Papers were selected on the basis of their content and their data used for discussion. RESULTS: Neurodevelopmental and behavioural data point to the possibility of involvement of the Wnt pathway in the pathophysiology of mood disorders. Clinical and post-mortem data are not sufficient to corroborate a definite role for Wnt alterations in any mood disorder. Combining genetic and pharmacological data, we may state that glycogen synthase kinase is the key molecule in bipolar disorder, as it is connected with many other signalling pathways that were shown to be involved in mood disorders, while Wnt molecules in the hippocampus appear to be mainly involved in depressive disorders. CONCLUSIONS: Altered Wnt signalling may play a role in the pathophysiology of mood disorders, although not a central one. It is premature to draw conclusions regarding the possible usefulness of Wnt manipulations in the treatment of mood disorders.

Increased serum Dickkopf-1 levels in drug-abusing psychotic patients.

BACKGROUND: Dickkopf-1 (DKK1) is an inhibitor of the canonical Wnt pathway, which is known to be impaired in both psychotic and neurodegenerative disorders. Here, we examined serum DKK1 levels as an indicator of ongoing neurodegeneration in psychotic patients, with or without a recent or current history of drug abuse. METHODS: We measured serum DKK1 levels by ELISA in 22 inpatients with psychosis and no history of drug abuse, 22 with psychosis and drug abuse, and 16 controls. We rated psychopathology using the following rating scales: the Positive and Negative Syndrome Scale (PANSS); the Clinical Global Impressions (CGI) severity scale; and the Global Assessment of Functioning (GAF) scale. Extrapyramidal motor symptoms were assessed by the Simpson-Angus Neurological Rating Scale (NRS). RESULTS: Inpatients with psychosis and comorbid substance abuse showed significantly higher serum DKK1 levels than inpatients with psychosis and no comorbid substance abuse or controls. Comorbid patients had earlier onset, longer duration of psychosis, and more severe extrapyramidal motor symptoms. However, we did not find any significant correlation between DKK1 levels and rating scale scores. CONCLUSION: Psychosis led to elevated serum DKK1 levels, and substance abuse led to a further increase. Knowing that there is a correlation between brain and blood levels of DKK1, we speculate that the observed increase in DKK1 levels reflects drug-induced neurotoxicity in our patients.

Hemochromatosis-induced bipolar disorder: a case report.

OBJECTIVE: A patient presenting with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, bipolar disorder was found to be affected by high iron hemochromatosis. This prompted us to explore the relation between bipolar disorder and iron overload. METHOD: We report the case and review the peer-reviewed literature focusing on mood symptoms in patients with hemochromatosis or iron overload. Animal studies of brain effects of iron overload are summarized. High iron hemochromatosis was confirmed by genetic testing, and treatment was instituted to address iron overload. RESULTS: Patient's bipolar symptoms completely subsided after phlebotomic reduction of iron overload. CONCLUSION: Clinicians should explore the possibility of iron overload and seek genetic confirmation of hemochromatosis in resistant bipolar disorder to avoid unnecessary medication.