Bakgrund: Psykisk ohälsa är ett starkt växande folkhälsoproblemen i västvärlden. Depression klassas som en av de mest krävande sjukdomar att leva med. Behandlingar som vanligen används vid depression är kognitiv beteendeterapi och medicinering med SSRI. Syfte: Att belysa hur SSRI eller kognitiv beteendeterapi upplevs av patienter med depression utifrån ett livsvärldsperspektiv. Metod: Kvalitativ litteraturstudie med induktivt synsätt där artiklarna analyserats utifrån en kvalitativ innehållsanalys. Resultat: Rädslan av biverkningar vid medicinering med SSRI är frekvent samt förekomsten av stigmatisering. Trots detta finns också upplevelser av att medicinen räddat patienters liv. I början upplevs ofta KBT som svårt att ta till sig. Att lära sig hantera sina känslor och beteende samt genomföra hemläxor kan ses som påfrestande. Efter en tid av kognitiv beteendeterapi kan både hemläxor och nyinlärda strategier ses som hjälp mot depressionen. Slutsats: Det fanns skilda upplevelser av de två behandlingsformerna. Det visade sig att ju fler KBT-sessioner patienterna gick på desto större effekt gav terapin. SSRI ansågs hjälpa över tid trots biverkningar som i början upplevdes som ett stort lidande.

Brainstem derived serotonin (5-HT) normally facilitates spinal motoneuron excitability and inhibits sensory afferent transmission and associated spinal reflexes. Because the 5-HT innervation of the spinal cord is almost exclusively derived from brainstem neurons, spinal cord injury leads to an immediate and dramatic loss of 5-HT and this in turn leads to the simultaneous loss of motoneuron excitability and increase (disinhibition) of sensory afferent transmission. This thesis examined how spinal cord 5-HT receptors adapt over the months after SCI (chronic injury) to compensate for the loss of 5-HT. We showed that after SCI 5-HT2B and 5-HT2C receptors become constitutively active (active in the absence of 5-HT) with chronic injury, and this leads to a recovery of motoneuron excitability and contributes to the recovery of locomotor function. Unfortunately, this also contributes to the development of muscle spasms when combined with the disinhibition of sensory afferent transmission. In contrast, 5-HT1 receptors that modulate sensory afferent transmission do not become constitutively active after chronic SCI, and this contributes to the continued disinhibition of sensory afferent transmission and associated hyperreflexia and muscle spasms after chronic SCI. However, exogenous application of 5-HT1B and 5-HT1F receptor agonists can restore inhibition over sensory afferent transmission and ultimately reduce muscle spasms. In summary, 5-HT2 receptors exhibit a remarkable adaptation to the loss of 5-HT with SCI, whereas 5-HT1 receptors do not. Understanding and promoting this natural plasticity may help in the development of better therapeutic interventions for treating SCI.

Rationale: The serotonergic system is involved in the modulation of emotion and plays an important role for personality and vulnerability for psychiatric disorders. In the papers included in this thesis, we investigate three biological factors that have been studied in relation to psychiatric symptoms: Platelet monoamine oxidase B (MAO-B) activity, and variations in the MAO-A and the serotonin transporter (5HTT) genes. We also study intensity dependent auditory evoked potentials (IAEP) as an intermediate phenotype for serotonergic capacity. Platelet MAO-B has been shown to be a biological marker for the properties of monoamine systems, with low activity being associated with vulnerability for high scores of sensation seeking, monotony avoidance, and impulsiveness, as well as for susceptibility for alcoholism. Functional polymorphisms in the promoter of the genes encoding MAO-A and the serotonin transporter result in high- or low- activity alleles that have been associated with numerous psychiatric symptoms. One hypothesis for the shaping of personality is that these genotype variants have prenatal effects on the wiring of the brain. Thus, exploring how the development of the brain is affected by different prenatal serotonin levels is relevant in this context. Observations: (i) Platelet MAOB activity was associated with monoamine metabolites in cerebrospinal fluid from cisterna magna in monkeys, as well as with voluntary alcohol intake, alcohol-induced aggression, and alcohol sensitivity. (ii) The long 5HTTLPR allele was associated with increased IAEP. (iii) The functional MAOA and 5HTT polymorphisms were associated with symptoms of ADHD-related traits in a population based sample of Swedish adolescents. Associations of these candidate genes with ADHD scores were strenghtened when the platelet MAOB activity was combined with genotype. (iv) Our pilot data showed that treatment of pregnant mice with 5HTT blocking antidepressives resulted in more serotonergic cellbodies in lateral wings of dorsal raphe in the offspring, when compared to saline treatment. Conclusions: Our studies support the notion that platelet MAOB activity and IAEP are endophenotypes for monoaminergic capacity and related behaviours. The functional candidate polymorphisms in MAOA and 5HTT were linked to behaviour, however, the cause-relationship is unclear and the explanation for the associations need to be further investigated, possibly with focus on prenatal effects of the polymorphisms.

Parkinson’s disease is a common neurodegenerative disorder caused by nigrostriatal dopamine loss, with motor deficiencies as the primary outcome. To increase the striatal dopamine content, patients are treated with 3,4-dihydroxyphenyl-l-alanine (l-DOPA). Beneficial relief of the motor symptoms is achieved initially, although the efficacy is lost with time and severe side effects, referred to as l-DOPA-induced dyskinesia, manifest in the majority of patients. Biological mechanisms responsible for the dopaminergic degeneration and the upcoming of dyskinesia are still unclear, and thus knowledge regarding critical factors for maintenance of the nigrostriatal system as well as neurochemical changes upon chronic l-DOPA is urgent. The present work aims at studying the importance of glial cell line-derived neurotrophic factor (GDNF) for nigrostriatal preservation, and the involvement of the dopaminergic, serotonergic, and glutamatergic systems in l-DOPA-induced dyskinesia. Effects from different levels of GDNF expression were evaluated on fetal mouse nigrostriatal tissue in a grafting study. In GDNF gene-deleted grafts, degeneration of the entire nigrostriatal system was evident at 6 months. In grafts with partial GDNF expression, significant loss of dopamine neurons was observed at later time points, although deviant findings in the dopamine integrity such as reduced innervation capacity and presence of intracellular inclusions-like structures were already present at earlier stages. The results emphasize GDNF as a crucial factor for long-term maintenance of the nigrostriatal system. Furthermore, striatal neurochemical alterations upon chronic l-DOPA treatment were studied in hemiparkinsonian rats using in vivo voltametry. The findings demonstrated impaired dopamine as well as glutamate releases in dyskinetic subjects, with no effects from acute l-DOPA administration. Conversely, in l-DOPA naïve dopamine-lesioned animals, dopamine release was increased and glutamate release attenuated upon a l-DOPA challenge. Moreover, l-DOPA-derived dopamine release was demonstrated to originate from serotonergic nerve fibers in the dopamine-lesioned striatum, an event that contributes significantly to dopamine levels also in intact striatum, and thus, is not a consequence from dopamine depletion. Assessment of serotonergic nerve fibers in l-DOPA treated animals and in a grafting study concluded that nerve fiber density was not affected by chronic l-DOPA treatment, nevertheless, dysfunction of this system can be suspected in dyskinetic animals since dopamine release was impaired and regulation of glutamate release by serotonergic 5-HT1A receptor activation was achieved in normal but not in dyskinetic animals. Furthermore, the selective serotonin reuptake inhibitor, fluoxetine, attenuated l-DOPA-induced dyskientic behavior, an effect that was demonstrated to be mediated via 5-HT1A receptors. In conclusion, dysmodulation of multiple transmitter systems is evident in LID.

Huntington’s disease (HD) is an inherited neurodegenerative disorder that is caused by a mutation of a single gene, huntingtin. The disease is more commonly known for the characteristic choreiform movements that develop in the later, more advanced stages of the disease. However, cognitive deficits and psychiatric symptoms are frequently observed prior to the onset of the motor symptoms. Little is known about the pathological bases for the neuropsychiatric features which include increased irritability and heightened aggression. Depression affects 30-50% of HD patients and is the most commonly diagnosed psychiatric symptom. This is proportionally higher than in the general population and it is possible that inherent pathological changes in the HD brain render a HD-gene positive individual more susceptible to depression. / Using a variety of behavioural tests, the R6/1 transgenic mouse model of HD was found to display altered responses reflective of depression-related behaviour, indicating that the HD mutation confers a genetic susceptibility for developing depression. The behavioural alterations were more robust in female HD mice reflecting a possible sex-dependent manifestation of the depression symptoms in the human HD population that has yet to be investigated. The onset and rate of progression of HD is strongly influenced by the environment and the development of depression is similarly impacted upon by environmental factors (e.g. stress, negative life events). The experimental paradigms of environmental enrichment and wheel-running slow the development of motor and cognitive symptoms in R6/1 HD mice and the present study reports that both paradigms also correct the depression-related behavioural phenotype. This study also found that HD mice had muted responses to two common classes of antidepressant drugs, highlighting the need for a detailed examination of the efficacy of drug treatments in HD patients. / Depression susceptibility is linked to genetic variance in the human population and studies of gene candidates in mutant mice report the detection of behavioural phenotypes similar to the present study. The depression-related behavioural phenotype of the R6/1 HD model was found to be associated with early down-regulations in mRNA levels of the ii serotonin (5-HT) 1A and 5-HT 1B receptors in the cortex and the hippocampus. Additionally, female HD mice had reduced cortical 5-HT transporter gene expression. Collectively, these findings indicate that a disruption of serotonergic signaling in the HD brain contributes to the development of depression in HD. Brain-derived neurotrophic factor (BDNF) gene expression is down-regulated in the HD brain, however the expression pattern of exon-specific splice variants was previously unknown. This study reports that BDNF mRNA levels are reduced in the hippocampus by an early age but also reports that individual exon-specific transcripts are differentially down-regulated in males and females, although the functional relevance of this remains to be investigated. / Overall, this study has demonstrated that the R6/1 transgenic mouse model of HD is ideal for further investigating the occurrence of depression in pre-motor symptomatic HD. It has also identified alterations in gene expression of key components of neuronal signaling which might be linked to the molecular basis of depression.

München, Techn. University, Diss., 2007.

Techn. University, Diss., 2005--Darmstadt.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 4 uppsatser.

Diss. (sammanfattning) Umeå : Univ., 2004. / Härtill 4 uppsatser.

Thesis (Ph. D. in Chemistry)--Vanderbilt University, Dec. 2008. / Title from title screen. Includes bibliographical references.