Familial differences in lithium responsive versus lithium nonresponsive psychoses

Psychiatric life histories of 218 first degree family members of 16 lithium responsive and 33 lithium non-responsive psychotic (mood incongruent) probands were contrasted. While the morbid risk of schizophrenic spectrum disorder was 9.8% in the 142 relatives of lithium nonresponsive probands, no cases of schizophrenic spectrum disorder were found among the 76 first degree relatives of lithium responsive psychotics (p less than 0.03). Lithium responsive psychotic illnesses appear to be familially, and perhaps genetically distinct from the bulk of the schizophrenias.     

Mood-incongruent versus mood-congruent psychosis: differential antipsychotic response to lithium therapy

The authors previously reported that a subgroup of schizophrenic-like patients respond favorably to lithium (Li) therapy, as do patients with a classical manic illness. In the present study, the time course of psychotic and affective symptom remission after Li therapy was examined in these two groups of patients. Li responsive patients with a mood-incongruent psychosis (schizophrenic-like illness) demonstrated a rapid antipsychotic response to Li therapy, showing a 50% improvement during the first 7 days, while no improvement in affective symptoms was seen until week 2 or 3 of treatment. Alternatively, patients with a mood-congruent psychosis (where mania is the primary diagnosis) demonstrated no antipsychotic response to Li therapy during the first 2 weeks of treatment, while some improvement in manic symptoms occurred during treatment week 2. The present study demonstrates that Li therapy differentially affects psychotic symptoms in mood-incongruent as opposed to mood-congruent psychosis. Further, the growth hormone (GH) response to apomorphine administration differentiated these two groups of Li responsive patients. Patients with a Li responsive mood-incongruent psychosis demonstrated over a seven-fold greater GH response than mood-congruent psychotic patients. The present data suggest that mood-incongruent and mood-congruent psychoses may represent two biologically distinct psychotic processes separable by both medication response and central dopamine function.     

Cabergoline-induced psychotic exacerbation in schizophrenic patients

INTRODUCTION: Hyperprolactinemia is a well-recognized side effect of antipsychotic treatment. Cabergoline, a dopamine agonist, has been introduced on the market to treat hyperprolactinemia, even secondary to antipsychotic use. CASE REPORT: In this article, we described two schizophrenic patients who received cabergoline to treat their antipsychotic-induced hyperprolactinemia and developed a subsequent psychotic exacerbation. The first patient received amisulpride as antipsychotic medication, and the second one took risperidone and fluoxetine for her psychotic and depressive symptoms, respectively. Both patients improved significantly their psychotic symptoms in 1 week without changing their former antipsychotic regimens. DISCUSSION: To the best of our knowledge, we found no previous report of cabergoline-induced psychotic exacerbation in schizophrenic patients who received antipsychotics. We brought up questions whether schizophrenic patients on amisulpride or with the addition of fluoxetine may have higher risk to experience psychotic worsening. We also highlighted the possible role of dose-dependent nature in cabergoline-induced psychotic exacerbation, suggesting that the single starting dose of 0.5 mg or higher might be unsafe in schizophrenic patients. CONCLUSION: These cases suggest that cabergoline, like other dopaminergic agents, should be used with caution in psychotic patients and the dose should be as low as possible.     

Abnormalities of lithium transport across the erythrocyte membrane in depression and schizophrenia

Three mechanisms of lithium transport across erythrocyte membrane [lithium-sodium countertransport (LSC), lithium-potassium cotransport (LPC), and passive lithium diffusion (PLD)] were estimated in 27 acutely schizophrenic patients, 27 acutely depressed affective patients and in 18 control subjects. The activities of all mechanisms studied were significantly lower in both schizophrenic and depressed patients compared with controls. Analysis by gender showed that in control subjects, mean values of erythrocyte LSC and LPC were significantly higher in males compared with females. The decrease of LSC and LPC in depression and LSC in schizophrenia compared with control subjects was observed only in male patients but not in female ones. The results obtained suggest that lithium transport abnormalities during acute psychotic episodes are not specific to affective patients where lithium exerts its therapeutic action, but are also observed in schizophrenia. These abnormalities are more evident in male patients.     

Lithium and chlorpromazine in psychotic inpatients

A sample of recently hospitalized psychotic patients was assigned to treatment with lithium or chlorpromazine in a double-blind drug trial. Several diagnostic systems were used to characterize the patients. No relationship was found, regardless of criterion system used, between dignosis and differences in drug effectiveness; specifically, the presence of “schizophrenic” symptoms did not predict a poor response to lithium. Among patients with physical overactivity, those treated with lithium terminated earlier and had poorer outcome than those treated with chlorpromazine. In patients who were not overactive, the two drugs were equally effective, and chronically psychotic patients had poorer outcomes regardless of drug. Lithium may be an effective treatment for acutely psychotic patients who are not overactive. The use of a lithium trial as a diagnostic tool may be unwarranted.     

Case studies of adjunctive agents in clozapine-resistant schizophrenic patients

Approximately 40%-70% of neuroleptic-resistant schizophrenic patients are nonresponders even to clozapine. Several clozapine augmentation strategies have come into clinical practice, although often without evidence-based support. This study aims to critically review all the reported case studies regarding the efficacy and safety of adjunctive agents in clozapine-resistant schizophrenic or schizoaffective patients. All published case studies examining the efficacy and safety of adjunctive agents in clozapine-resistant schizophrenic patients were searched for in the MEDLINE database from January 1980 to February 2004. Case studies regarding ECT as a clozapine augmentation strategy were not included in our study. All the included papers were critically reviewed and examined against a set of clinical and pharmacological parameters, outcome measures, and reported side effects. Fifteen case studies regarding the efficacy and safety of sulpiride, risperidone, olanzapine, lithium, lamotrigine, fluvoxamine, and bromocriptine as clozapine adjuncts were found. A total of 33 schizophrenic or schizoaffective patients were included. Of the 15 studies, 8 were associated with risperidone. The duration and dosage of previous clozapine monotherapy was adequate for 16 patients. Plasma clozapine level was assessed for only 7 patients. Outcome measures were used for only 11 patients. The outcome was positive in 13 studies. Combined treatments were generally well tolerated, and side effects never resulted in discontinuation of treatment. Most case studies favor the use of risperidone as an adjunctive agent in clozapine-resistant schizophrenic or schizoaffective patients. However, small numbers of patients and other methodological shortcomings limit the impact of evidence provided.     

The use of psychotropic agents in pregnancy and lactation

The question of which psychotropic medications are safe during pregnancy is likely to remain unanswered for many years to come. There are ethical limitations to performing the type of prospective controlled studies required to answer a scientific question of this type definitively. At the present time, in all patients with worsening psychiatric illness during pregnancy, be it in the schizophrenic, affective, anxiety disorder, or personality disorder spectrum, outpatient psychotherapy, hospitalization, and milieu therapy should be attempted prior to the routine use of psychotropic medication. Prior to pregnancy, withdrawal of psychotropic medications should be attempted under close supervision. Situations will arise in which hospitalization is not sufficient to avert psychotic decompensation. In both schizophrenic illnesses and acute mania, neuroleptics should be used, especially in the first trimester in preference to lithium. The use of high-potency neuroleptics appears preferable to low-potency agents as the first line of therapy, although subsequent management decisions will depend on ability to control side effects. In depression, TCAs should be used in cases of suicidality or incapacitating vegetative signs after the first trimester if supportive measures fail. There appears to be no rationale for withdrawal of TCAs prior to labor. In the third trimester, use of TCAs, low-potency neuroleptics, or lithium should be accompanied by obstetrical surveillance. In severe anxiety or insomnia following the first trimester, the occasional use of benzodiazepines may be warranted except during labor and the first week postpartum. The chronic use of benzodiazepines during any phase of pregnancy and in breastfeeding women is contraindicated. The importance of close rapport between the treating physician and the pregnant or breastfeeding patient cannot be overstated and will obviate or decrease reliance on psychotropic medication in many cases.     

Remoxipride in schizophrenia. A preliminary report

Remoxipride, a substituted benzamide with preferential action on mesolimbic dopaminergic brain functions, was investigated in an open study in 10 schizophrenic patients. After 1 week with placebo, patients received remoxipride in a increasing doses from 150 to maximal 450 mg daily for 6 weeks. In six patients a clinically relevant reduction of psychotic symptomatology as assessed with the BPRS was observed. Few adverse effects were noted; extrapyramidal symptoms, if present, decreased during treatment, while the reported side effects were only mild. No consistent changes in plasma levels of prolactin and HVA were found.     

Recovery from schizophrenic psychosis

Knowledge of changes in patients' symptoms during hospitalization is crucial in planning treatment for acute psychotic exacerbation of chronic schizophrenia. Biweekly assessment of symptoms in 44 schizophrenic patients during the first 4 weeks of hospitalization showed that rapid recovery from psychotic symptoms occurred early in hospitalization; recovery from depression and anxiety was less complete. The rapid recovery in the first few weeks of hospital treatment supports the use of brief hospitalization for psychotic relapse. It is important to focus follow-up treatment on patients' relative lack of recovery in the hospital from depression and anxiety.     

Age-of-onset of schizophrenic and obsessive-compulsive symptoms in patients with schizo-obsessive disorder

Obsessive-compulsive symptoms (OCS) are prevalent, persistent, clinically significant phenomena in schizophrenia. To facilitate the understanding of their temporal interrelationship, we assessed age-of-onset of schizophrenic and obsessive-compulsive symptoms among 133 patients admitted to Tirat Carmel Mental Health Center (Israel) during the years 1999-2010 who met DSM-IV criteria for both schizophrenic disorder and obsessive-compulsive disorder (OCD). The mean age-of-onset of the first clinically significant OCS was significantly earlier than the mean age-of onset of the first psychotic symptoms. An earlier onset of OCS was detected in men, but not in women. In sixty-four of 133 patients OCS preceded the first psychotic symptoms, in 37 patients OCS followed them, and in 32 patients OCS and psychotic symptoms occurred simultaneously. A sub-analysis of 52 first-episode schizophrenia patients revealed that OCS emerged approximately 3 years earlier than psychotic symptoms. Notably, schizo-obsessive patients had earlier mean age-of-onset of first psychotic symptoms than a comparative group of 113 non-OCD schizophrenia patients matched for age, gender and number of hospitalization. Earlier emergence of OCS than schizophrenic symptoms in schizo-obsessive patients suggests that they are independent of psychosis and are not consequent to schizophrenia. In addition, the presence of OCS seems to modify clinical features of schizophrenia accounting for earlier onset of first psychotic symptoms, however a replication of these findings is needed.     

Hopelessness and first-episode psychosis: a longitudinal study

Hopelessness has not been adequately studied in first-episode psychotic patients, although it is already present at the early stages, especially in schizophrenic patients. We have studied 96 neuroleptic-naive psychotic patients (49 schizophrenic patients and 47 other non-affective psychotic patients) over a period of 12 months after their first admission. The total score on the Hopelessness Scale (HS) at first admission was higher in the schizophrenic patients, and correlated with younger age and with negative symptoms. High HS scores at baseline predicted poor short-term outcome in schizophrenic patients, as evidenced by worse global functioning at the 12-month follow-up. These correlations were not observed in the other psychoses group. Our results suggest that young, severely affected schizophrenic patients who experience hopelessness might be at higher risk of poor outcome.     

Lithium response and psychoses: a double-blind, placebo-controlled study

Lithium-associated remission of psychosis has been described in schizophreniform disorders and in psychotic patients with variants of the red blood cell (RBC)/lithium ratio. To determine whether such remissions are the consequence of lithium treatment rather than spontaneous in nature, a double-blind, placebo-controlled study was undertaken in 16 psychotic patients preselected for the variant of RBC/lithium ration and/or DSM-III schizophreniform diagnosis. Essentially full and sustained remission of psychosis began during periods of lithium treatment in 4 of 15 of the study patients. Improvement was significantly greater during lithium treatment periods than in counterbalanced placebo treatment conditions in these four subjects (p less than 0.02). Fifteen of the same 16 study patients failed to initiate sustained improvement either spontaneously or while on placebo during the initial 14-day treatment period. In this preselected psychotic population, sustained response to lithium occurred at a rate at least four times greater than that which could be attributed to spontaneous remission.     

Clinical correlates of platelet prostaglandin receptor subsensitivity in schizophrenia

A diminished cAMP response to prostaglandin E1 (PGE1) in platelets from schizophrenic patients has been demonstrated previously. The authors report that among 35 actively psychotic male schizophrenic patients, the platelet cAMP response to PGE1 was negatively correlated with global symptom severity and with several indexes of positive symptom severity but not with negative symptom severity. If this subsensitivity of platelet PGE receptors extends to brain PGE receptors, schizophrenic patients may have an impairment in the ability of endogenous PGEs to inhibit dopaminergic transmission. Such impairment could have a permissive effect on the production of psychotic symptoms during exacerbations in schizophrenic patients.     

The pharmacotherapy of depressive illness in adolescence: II. Effects of lithium augmentation in nonresponders to imipramine.

The antidepressant value of lithium augmentation was assessed in a 3-week open trial involving 24 adolescents who remained highly depressed after 6 weeks of treatment with imipramine hydrochloride. Two patients responded dramatically during the first week, with an additional eight patients showing partial improvement during the 3-week trial. The overall magnitude of improvement in depression ratings was significantly greater than in an historical control group of nonresponders who continued to receive imipramine monotherapy during their hospital treatment. Results suggest the potential use of this adjunctive strategy in some tricyclic resistant adolescent depressives, although it appears less efficacious overall in this age group than in adults.     

Adjunctive antipsychotic treatment is necessary for adolescents with psychotic mania

Adolescents with acute psychotic mania were treated with lithium and adjunctive haloperidol as part of a lithium efficacy study. If the psychosis completely resolved, haloperidol was discontinued after 1 week of therapeutic lithium levels. Our first five subjects experienced a rapid exacerbation of symptoms, which responded to restarting haloperidol. A longer duration of adjunctive antipsychotic treatment is necessary in adolescents with bipolar psychosis.     

Vitamin B6 as add-on treatment in chronic schizophrenic and schizoaffective patients: a double-blind, placebo-controlled study

BACKGROUND: Vitamin B6, or pyridoxine, plays an intrinsic role in the synthesis of certain neurotransmitters that take part in development of psychotic states. Several reports indicate that vitamin B6 may be a factor in a number of psychiatric disorders and related conditions, such as autism, Alzheimer's disease, hyperactivity, learning disability, anxiety disorder, and depression. Moreover, there are anecdotal reports of a reduction in psychotic symptoms after vitamin B6 supplementation of psychopharmacologic treatment of patients suffering from schizophrenia or organic mental disorder. The aim of this study was to examine whether vitamin B6 therapy influences psychotic symptoms in patients suffering from schizophrenia and schizoaffective disorder. METHOD: The effects of the supplementation of vitamin B6 to antipsychotic treatment on positive and negative symptoms in 15 schizophrenic and schizoaffective patients (DSM-IV criteria) were examined in a double-blind, placebo-controlled, crossover study spanning 9 weeks. All patients had stable psychopathology for at least 1 month before entry into the study and were maintained on treatment with their prestudy psychoactive and antiparkinsonian medications throughout the study. All patients were assessed using the Positive and Negative Syndrome Scale (PANSS) for schizophrenia on a weekly basis. Patients randomly received placebo or vitamin B6, starting at 100 mg/day in the first week and increasing to 400 mg/day in the fourth week by 100-mg increments each week. RESULTS: PANSS scores revealed no differences between vitamin B6- and placebo-treated patients in amelioration of their mental state. CONCLUSION: Further studies with larger populations and shorter duration of illness are needed to clarify the question of the possible efficacy of vitamin B6 in treatment of psychotic symptoms in schizophrenia.     

Lithium carbonate treatment of mania. Cerebrospinal fluid and urinary monoamine metabolites and treatment outcome

Treatment of manic patients with lithium carbonate was associated with significant decreases in cerebrospinal fluid (CSF) 3-methoxy-4-hydroxyphenylglycol (MHPG) and urinary norepinephrine excretion. These measures, before treatment, were higher in manic patients than in either depressed or normal subjects and correlated significantly with severity of mania. Levels in CSF of homovanillic acid and 5-hydroxyindoleacetic acid did not correlate with severity or with change during lithium carbonate treatment. Responders (about 70% of the patients) did not differ from nonresponders in pretreatment mania ratings or neurotransmitter measures. The CSF MHPG and urinary norepinephrine excretion were reduced during lithium carbonate treatment in both responders and nonresponders. Unlike the case before treatment, urinary MHPG excretion was higher during treatment in nonresponders than in responders and correlated with several indexes of symptom severity. These results support a relationship between mania and increased noradrenergic function. Treatment outcome, however, was not related exclusively to the reduction of noradrenergic indexes by lithium carbonate since reductions were similar in both responders and nonresponders. Reduced noradrenergic activity may therefore be necessary but not sufficient for successful outcome during lithium carbonate treatment.