Antidepressant up-titration: pharmacological and psychological considerations

Abstract

The use of antidepressant up-titration in starting therapies is useful in reducing side effects, but can induce delays in clinical response. Several aspects concerning slow or more aggressive titration have to be considered when using this strategy, such as pharmacological aspects (e.g., synaptic up-regulation) and psychological/clinical aspects (e.g., adherence to antidepressant treatment, and the temperament and expectations of patients). Data from the literature are controversial, and so the choice between rapid and slow titration must be tailored more to the patient, rather than to the drug.

Keywords::

• antidepressants
• titration

Several papers have discussed whether the use of antidepressant up-titration in a starting therapy is an advantageous strategy, particularly in reducing side effects, or a disadvantageous one, because of the delay in clinical response due to later achievement of therapeutic dosages [1-4]. As a matter of fact, the 2 – 3-week latency of the antidepressant response is well-known and represents one of the current clinical problems of these medications, in that it prolongs the impairments associated with depression and leaves patients at risk for suicide. Besides, the early appearance of side effects in the same latency period favors a high rate of discontinuation in the first weeks of antidepressant treatment [5-7]. Slow antidepressant up-titration can reduce the appearance of the side effects linked to excessively fast increase of neurotransmitters and thus improve adherence to treatments. On the other hand, a slow dosage increase can postpone the achievement of therapeutic dosages, thus delaying a clinical response.

The aspect of adherence to treatments is of primary importance in the context of titration. The World Health Organization (2003) [8] proposed five groups of factors reducing adherence to therapies: patient-related, condition-related, therapy-related, social/economic-related, and health-care team/system-related. The biopsychosocial model (BPSM) is in agreement with this WHO suggestion applied to therapeutic treatments, and posits that biological, psychological (entailing thoughts, emotions, and behaviors), and social factors all play a significant role in the context of the disease manifestations or its treatments [9]. Applied to the question of adherence, the BPSM offers a holistic evaluation of the biological aspects, which are mostly related to a medical approach to patient adherence and closely linked to psychological factors influencing and sometimes triggering the biological ones. Biological and psychological factors are both entered into a social context (familial, relational, socio-medical, etc.) that acts as a positive or negative resonance box for biological and emotional factors.

This dilemma concerning slow or more aggressive titration of antidepressants has to be considered from two different points of view: the pharmacological and the psychological/clinical.

On the basis of the monoamine hypothesis of depression, a patient with a mood disorder is characterized by a reduction in serotonergic, noradrenergic, or dopaminergic transmission. This hypothesis has evolved over time, including other pathological factors such as neurotransmitter receptor hypothesis, neurotrophic factor hypothesis, hypothalamic–pituitary–adrenal (HPA) dysregulation, oxidative stress, cytokine hypothesis and NO pathways [10]. The reduction of a neurotransmitter induces receptorial changes at the synaptic level, for example, up-regulation of postsynaptic receptors, in order to compensate for the transmettitorial deficit. In turn, up-regulation causes higher sensitization to the release of a neurotransmitter induced by the antidepressant inhibition of reuptake, until down-regulation of the postsynaptic receptors takes place. So in the first phase of the treatment, excessive release of, for example, serotonin, can over-stimulate receptor subtypes inducing nausea, hyperhidrosis, or tremors. On the other hand, if the increase of a neurotransmitter takes place gradually, postsynaptic stimulation will be less intense, thus reducing potential side effects. This fact can provide a pharmacological explanation for a worsening of anxiety observed in the first phases of treatment in some panic or obsessive patients when initially treated with aggressive doses of SSRIs [11]. In patients with anxiety disorders, slow titration could be more useful with respect to depressive patients according to hyper-activation of the monoaminergic systems observed in anxiety disorders. On the other hand, hyper-activation of the HPA axis is also present in depressed patients, justifying the same interpretative model [10]. In addition, increased sensitivity to side effects, and therefore to fast titration, is more frequent in drug-naive patients than to multi-treated or long-term treated patients [12].

From the psychological and clinical point of view, the effectiveness of a treatment is a multifactorial concern in which the efficacy of the drug is the major contributor, although its tolerability and safety are also important. When tolerability is reduced, effectiveness is also compromised, particularly when patient motivation to the treatment is low: this is the case when awareness of the pathology is reduced or when expectation concerning side effects is elevated. In these situations, the risk of low adherence is very high and the appearance of side effects can favor discontinuation.

Temperamental factors can also come into play. Genetically-related temperaments, such as novelty seeking and harm avoidance, may influence medication adherence behavior. Novelty seeking (NS), the tendency toward exploratory activity in response to novelty, lack of inhibition and impulsiveness is hypothetically related to dopaminergic activity.

Modification of the dopamine receptor gene (D4 receptor exon III) can reduce such a personality trait [13]. Novelty-seeking strengthens adherence in several pathologies, particularly when there is sufficient awareness of the disease. On the other hand, alteration of serotonergic genes favors the development of a harm-avoidance temperament. Harm avoidance (HA), the tendency to anxiety, shyness, worry and avoidance of punishment, is hypothetically related to serotonergic activity. HA increases the susceptibility to side effects and consequently lowers adherence [14]. Thus a subject characterized by a novelty-seeking temperament, accepting detrimental side effects in view of a further advantage, is more adherent to treatment than an individual with a harm-avoidant temperament, which emphasizes current side effects without good expectation of further clinical improvement.

The data from the literature concerning slow or fast up-titration are controversial: some papers confirm the utility of slow up-titration [3,4], while others support the nonclinical advantage of titration and suggest a more aggressive pharmacological behavior [1,15].

In this issue, Dr Wilhelm et al., in a post-hoc analysis of a multicenter, prospective, non-interventional, 6-month study in adult outpatients with a depressive episode, pointed out that a starting dose of 60 mg of duloxetine was not associated with poorer tolerability than a starting dose of 30 mg in a large cohort (4517 patients enrolled) of depressed patients with co-existing somatic illnesses [15]. But, patients that started with 30 mg/day (72.7%) presented more somatic disease, and consequently a higher risk of side effects than patients starting with 60 mg/day.

In a sample of 60 patients with panic disorder, Buoli et al. (2010) [3] assessed differences in terms of effectiveness and tolerability between slow up-titration with paroxetine (increments of 2.5 mg/day every 2 days) versus standard titration (increments of 10 mg/day every week) up to a maximum daily dose of 20 mg. Post-hoc analysis found only one significant difference in the intensity of spontaneous panic attacks in the first 9 days, which was less intense in the slow-titration group (treatment effect: F = 4.89, p = 0.03, effect size = 0.1), whilst no differences between the two treatment regimens were found at end-point. Comparing a rapid sertraline titration regimen (150 mg/day reached at day 5 after beginning therapy) with a slow one (150 mg/day reached at day 15 after beginning therapy) in a pool of 32 patients with obsessive–compulsive disorder, Bogetto et al. (2002) [1] found that both titration regimens were effective in reducing OC symptoms and were well tolerated: no differences in drop-out on adverse event rates emerged between the two groups.

The problem is that the advantage or disadvantage of titration is more related to the patient than to the drug itself: in this case we also have to consider pharmacological aspects, such as gene polymorphism [16] or drug plasmatic levels [17], or the clinical aspect, for example, when dealing with a particular population [4]. In a frail population, such as the oncological one, Amodeo et al. (2012) [4] randomly assigned 30 consecutive cancer patients (F = 21; M = 9), meeting DSM-IV TR criteria for mood disorders (MD), to a slow (arm A) or standard (arm B) paroxetine titration. Both treatment groups showed a significant mood improvement (change in MADRS total score) from baseline to end-point (arm A-F(2,18) = 33.68 p < 0.001; arm B-F(2,12) = 6.97 p < 0.005). A significantly higher rate of patients in arm A compared with arm B showed no side effects after 2 weeks (40% vs. 6.7%, respectively). A multinomial logistic regression confirmed these differences between arms (chi-square = 20.89 p = 0.004); as did the self-evaluating scale (SIDE): side effects were perceived by 60% of subjects in arm B against only 11.1% of patients in arm A. In conclusion, the results of this study suggest that slow paroxetine up-titration is better tolerated and at least as effective as standard paroxetine up-titration in cancer patients with depression.

Slow up-titration is a good strategy with the elderly, too, allowing an effective dosage to be reached with a reduction in the appearance and/or severity of side effects, in accordance with the saying “start low and go slow” proposed in clinical geriatric practice [18].

It should be noted that some pharmacological considerations also have to take into account the need for slow titration, for example, differences between classes: tricyclics antidepressants need to be up-titrated because of the cardiac toxicity associated with peak plasmatic levels [19]; SSRIs or SNRIs can induce transitory side effects in the first phases of treatment which can be reduced with up-titration [4,20]; antidepressants with different mechanisms of action, such as agomelatine, demonstrate little need of titration.

The problem of low titration has also been investigated with other classes of psychiatric drugs, such as mood stabilizers: investigating whether the use of a loading strategy with lithium or valproate followed recommended practice, Wheeler and colleagues (2008) found that more adverse effects occurred with loading (51.2%) compared to titrating (36.0%), particularly with lithium [21]. It is important to remember that slow up-titration of lamotrigine is a must in order to avoid serious side effects [22]. In other pathologies, too, such as pain, slow titration is suggested by several authors [23].

In conclusion, Table 1 summarizes a list of factors to be taken into account in the choice of slow/fast titration.

Table 1. Factors orienting the choice of slow/fast titration.

Slow titration	Fast titration
Frail patients	Severe depressed patients
Somatic comorbid patients	Drug-resistant patients
Drug-naive patients	Long-term treated patients

Expert opinion

A loading strategy in antidepressant treatment can induce more side effects than a titrating strategy, thus inducing a higher rate of drop-out in the first weeks of treatment, when side-effects outnumber efficacy. This aspect is emphasized in frail populations, for example, geriatric or somatic comorbid patients. On the other hand, when the severity of the pathology is higher, for example, when a patient presents suicidal intentions, more aggressive intervention is needed, and titration is not suitable So the choice between rapid and slow titration must take into consideration not only pharmacological aspects but also cognitive (beliefs about treatment) and emotional ones (temperament, expectations) which, together, can influence adherence to antidepressant treatments and their effectiveness.

Declaration of interest

The author states no conflict of interest and has received no payment in preparation of this manuscript.