ABSTRACT
BACKGROUND: Cancer patients are disproportionately affected by generalized anxiety and major depression. For many, current treatments for these conditions are ineffective. In this case report, we present a serendipitous case of anxiety and depression improvement following administration of the poly (ADP-ribose) polymerase (PARP) inhibitor niraparib. CASE PRESENTATION: A 61-year old woman with a 20-year history of mild depression developed recurrent ovarian carcinoma and was placed on niraparib for maintenance chemotherapy. With the original onset of ovarian cancer, she experienced an episode of major depression that was resolved with sertraline. After recurrence of ovarian cancer, she experienced a recurrence of major depression and a new onset of generalized anxiety that failed to completely respond to multiple medications. After beginning niraparib therapy the patient noticed a rapid resolution of the symptoms of her anxiety and depression, an effect that was limited to 10-14 days. Due to bone marrow suppression, the patient was taken off and restarted on niraparib several times. Each discontinuation of niraparib resulted in return of her depression and anxiety, while each recontinuation of niraparib resulted in an improvement in her mood and anxiety. CONCLUSIONS: This case demonstrates rapid and temporary improvement of anxiety and depression following niraparib administration. There is ample preclinical data that PARP signaling may play a role in psychiatric illness. A small amount of indirect data from clinical trials also shows that niraparib may have psychiatric benefits. Further research on PARP inhibition and its potential psychoactive effects is sorely needed.
Subject(s)
Depression , Poly(ADP-ribose) Polymerase Inhibitors , Anxiety/drug therapy , Female , Humans , Indazoles , Middle Aged , Neoplasm Recurrence, Local/drug therapy , Piperidines , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic useABSTRACT
In this study, p-chlorophenylalanine (pCPA), an inhibitor of tryptophan hydroxylase (the rate limiting enzyme of serotonin synthesis), was used to reduce serotonin (5HT) levels during early development in zebrafish embryos. One day old dechorionated embryos were treated with 25 µM pCPA for 24h and subsequently rescued. Immunohistological studies using a 5HT antibody confirmed that 5HT neurons in the brain and spinal cord were depleted of transmitter by 2 days post fertilization (dpf). Twenty four hours after pCPA exposure embryos were unable to burst swim and were nearly paralyzed. Movement began to improve at 4 dpf, and by 7 dpf, larvae exhibited swimming activity. Rescued larvae continued to grow in rostrocaudal length over 5 days post-rescue, but their length was always 16-21% below controls. Surprisingly, both groups displayed the same number of myotomes. To examine whether hypertonicity of myotomes in treated embryos played a role in their shorter rostrocaudal lengths, 1 dpf embryos were exposed to a combination of 25 µM pCPA and 0.6 mM of the sodium channel blocker ethyl 3-aminobenzoate methanesulfonate (MS-222). After a 24 hour exposure, the embryos exhibited the same rostrocaudal length as control embryos suggesting that myotome hypertonicity plays a major role in the decreased axial length of the treated larvae. In addition, pCPA treated 2 dpf embryos exhibited abnormal notochordal morphology that persisted throughout recovery. Reverse transcriptase polymerase chain reaction (RT-PCR) was performed to determine the relative levels of the serotonin 1A receptor (5HT(1A)) transcript and the serotonin transporter (SERT) transcript in the brain and spinal cord of control and treated embryos. Transcripts were present in both brain and spinal cord as early as 1 dpf and reached maximal concentrations by 3 dpf. Embryos treated with pCPA demonstrated a decrease in the concentration of 5HT(1A) transcript in both brain and spinal cord. While SERT transcript levels remained unaffected in brain, they were decreased in spinal cord. Five days subsequent to pCPA rescue, 5HT(1A) transcript concentrations remained decreased in brain while SERT transcript levels were elevated in both regions. These findings suggest that reduction of 5HT during early zebrafish development may have an adverse effect on body length, notochordal morphology, locomotor behavior, and serotonin message-related expression.
Subject(s)
Serotonin Antagonists/toxicity , Serotonin/deficiency , Zebrafish/embryology , Animals , Body Patterning/drug effects , Body Patterning/physiology , Disease Models, Animal , Fenclonine/toxicity , Neural Pathways/drug effects , Neural Pathways/metabolism , Neural Pathways/physiopathology , Serotonin/genetics , Serotonin Plasma Membrane Transport Proteins/deficiency , Serotonin Plasma Membrane Transport Proteins/genetics , Tryptophan Hydroxylase/antagonists & inhibitors , Tryptophan Hydroxylase/metabolism , Zebrafish/genetics , Zebrafish/metabolismABSTRACT
One of the etiological theories of schizophrenia is dysregulation of the immune system. Autoantibodies specific for the alpha7 subunit of the nicotinic receptor could potentially contribute to the pathophysiology of the disease. In this study, positive antibodies specific for the receptor were found to exist in 23% of the patients diagnosed with schizophrenia (n=21). On the average, levels for the antibody were elevated in the schizophrenia patient population than in controls. The data also suggests that there is a significant correlation between antibody titer and age, lending support to the neurodegenerative nature of the disease.
Subject(s)
Antibodies/blood , Receptors, Nicotinic/immunology , Schizophrenia/blood , Schizophrenia/immunology , Age Factors , Aged , Autoantibodies/blood , Female , Humans , Male , Middle Aged , Receptors, Nicotinic/bloodABSTRACT
This study examines the effects of the selective serotonin reuptake inhibitor (SSRI), fluoxetine (PROZAC), on the ontogeny of spontaneous swimming activity (SSA) in developing zebrafish. The development of zebrafish motor behavior consists of four sequential locomotor patterns that develop over 1-5 days post fertilization (dpf), with the final pattern, SSA, established at 4-5 dpf. In stage specific experiments, larvae were exposed to 4.6 microM fluoxetine for 24 h periods beginning at 24 h post fertilization (hpf) and extending through 5 dpf. From 1-3 dpf, there was no effect on SSA or earlier stages of motor development, i.e., spontaneous coiling, evoked coiling and burst swimming. Fluoxetine exposure at 3 dpf for 24 h resulted in a transient decrease in SSA through 7 dpf with a complete recovery by 8 dpf. Larvae exposed to 4.6 microM fluoxetine for 24 h on 4 or 5 dpf showed a significant decrease in SSA by day 6 with no recovery through 14 dpf. Although SSA was significantly affected 24 h after fluoxetine exposure, there was little or no effect on pectoral fin movement. These results demonstrate both a stage specific and a long term effect of 4.6 microM fluoxetine exposure in 4 and 5 dpf larvae. Reverse transcriptase polymerase chain reaction (RT-PCR) was performed to determine the relative levels of a serotonin transporter protein (SERT) transcript and the serotonin 1A (5-HT(1A)) receptor transcript in developing embryos/larvae over 1-6 dpf. Both transcripts were present at 24 hpf with the relative concentration of SERT transcript showing no change over the developmental time range. The relative concentration of the 5-HT(1A) receptor transcript, however, showed a two-tiered pattern of concentration. RT-PCR was also used to detect potential changes in the SERT and 5-HT(1A) receptor transcripts in 6 dpf larvae after a 24 h exposure to 4.6 microM fluoxetine on 5 dpf. Three separate regions of the CNS were individually analyzed, two defined brain regions and spinal cord. The two brain regions showed no effect on transcript levels subsequent to fluoxetine exposure, however, the spinal cord showed a significant decrease in both transcripts. These results suggest a correlation between decreased concentration of SERT and 5-HT(1A) receptor transcripts in spinal cord and decreased SSA subsequent to fluoxetine exposure.
Subject(s)
Central Nervous System/metabolism , Embryo, Nonmammalian/drug effects , Fluoxetine/toxicity , Larva/metabolism , Movement Disorders , Selective Serotonin Reuptake Inhibitors/toxicity , Analysis of Variance , Animals , Behavior, Animal/drug effects , Central Nervous System/drug effects , Dose-Response Relationship, Drug , Female , Fertilization/drug effects , Gene Expression Regulation, Developmental/drug effects , Heart Rate/drug effects , Larva/drug effects , Locomotion/drug effects , Motor Activity/drug effects , Movement Disorders/etiology , Movement Disorders/metabolism , Movement Disorders/pathology , Receptor, Serotonin, 5-HT1A/metabolism , Serotonin/metabolism , Serotonin Plasma Membrane Transport Proteins/metabolism , Time Factors , ZebrafishSubject(s)
Depressive Disorder/therapy , Pregnancy Complications/therapy , Psychotherapy/methods , Antidepressive Agents/adverse effects , Antidepressive Agents/therapeutic use , Cognitive Behavioral Therapy/methods , Female , Humans , Practice Guidelines as Topic , Pregnancy , Pregnancy Outcome , Risk Assessment , Treatment OutcomeABSTRACT
We report on 3 subjects with premenstrual magnification of major depression (PMMD) treated with nefazodone who benefited from a supplement of additional nefazodone premenstrually. During the 6-month study, subjects were given supplements of either additional nefazodone or placebo prior to the expected onset of menses (double-blind crossover design). Symptoms were assessed during the late luteal and follicular phases. All subjects showed significant improvement for the months in which they received nefazodone supplements, but not when given placebo. Premenstrual dose increase is a clinically promising intervention for women who experience PMMD.
